Journal articles on the topic 'Smoothened signaling pathway'
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1
Kim, June Myoung, Hyeseung Han, Minjin Bahn, Yeokyu Hur, Chang-Yeol Yeo, and Dae-Won Kim. "Secreted tyrosine kinase Vlk negatively regulates Hedgehog signaling by inducing lysosomal degradation of Smoothened." Biochemical Journal 477, no. 1 (January 8, 2020): 121–36. http://dx.doi.org/10.1042/bcj20190784.
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Vlk is a secreted tyrosine kinase that plays crucial roles during vertebrate embryonic development including skeletal formation. Genetic studies suggest that Vlk can modulate the Hedgehog signaling pathway during skeletal development. Despite its potential roles as an extracellular regulator of signaling pathways, little is known regarding the molecular functions of Vlk. Here we show that Vlk can negatively regulate the Hedgehog signaling pathway. We found that Vlk can induce lysosomal degradation of Smoothened, a crucial transmembrane signal transducer of the Hedgehog pathway, through the interaction with the extracellular domain of Smoothened (Smo-ECD). In addition, we observed that Vlk can attenuate Hedgehog signaling-induced ciliary localization of Smoothened. Furthermore, Vlk-mediated suppression of Hedgehog signaling can be diminished by tyrosine-to-phenylalanine substitutions in Smo-ECD. Taken together, these results suggest that Vlk may function as a signaling regulator in extracellular space to modulate the Hedgehog pathway.
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Faria, Alessandra V. de S., Adamu Ishaku Akyala, Kaushal Parikh, Lois W. Brüggemann, C. Arnold Spek, Wanlu Cao, Marco J. Bruno, Maarten F. Bijlsma, Gwenny M. Fuhler, and Maikel P. Peppelenbosch. "Smoothened-dependent and -independent pathways in mammalian noncanonical Hedgehog signaling." Journal of Biological Chemistry 294, no. 25 (April 16, 2019): 9787–98. http://dx.doi.org/10.1074/jbc.ra119.007956.
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Hedgehog proteins are pivotal morphogens acting through a canonical pathway involving first activation of ligand binding to Patched followed by alleviation of Smoothened receptor inhibition, leading to activation of Gli transcription factors. Noncanonical Hedgehog signaling remains poorly characterized but is thought to be mainly dependent on Smoothened. However, Smoothened inhibitors have yielded only partial success in combating Hedgehog signal transduction–dependent cancer, suggesting that noncanonical Smoothened-independent pathways also are clinically relevant. Moreover, several Smoothened-dependent effects (e.g. neurite projection) do not require transcriptional activation, further suggesting biological importance of noncanonical Smoothened-dependent pathways. We comprehensively characterized the cellular kinome in Hedgehog-challenged murine WT and Smoothened−/− fibroblasts as well as Smoothened agonist–stimulated cells. A peptide assay–based kinome analysis (in which cell lysates are used to phosphorylate specific kinase substrates), along with endocytosis, Lucifer Yellow–based, and immunoblotting assays, identified an elaborate signaling network of both Smoothened-dependent and -independent pathways that mediates actin reorganization through Src-like kinases, activates various proinflammatory signaling cascades, and concomitantly stimulates Wnt and Notch signaling while suppressing bone morphogenetic protein (BMP) signaling. The contribution of noncanonical Smoothened-independent signaling to the overall effects of Hedgehog on cellular physiology appears to be much larger than previously envisioned and may explain the transcriptionally independent effects of Hedgehog signaling on cytoskeleton. The observation that Patched-dependent, Smoothened-independent, noncanonical Hedgehog signaling increases Wnt/Notch signaling provides a possible explanation for the failure of Smoothened antagonists in combating Hedgehog-dependent but Smoothened inhibitor–resistant cancer. Our findings suggest that inhibiting Hedgehog–Patched interaction could result in more effective therapies as compared with conventional Smoothened-directed therapies.
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Jeng, Kuo-Shyang, I.-Shyan Sheen, Chuen-Miin Leu, Ping-Hui Tseng, and Chiung-Fang Chang. "The Role of Smoothened in Cancer." International Journal of Molecular Sciences 21, no. 18 (September 18, 2020): 6863. http://dx.doi.org/10.3390/ijms21186863.
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Smoothened (SMO) belongs to the Hedgehog (HH) signaling pathway, which regulates cell growth, migration, invasion and stem cells in cancer. The HH signaling pathway includes both canonical and noncanonical pathways. The canonical HH pathway functions through major HH molecules such as HH ligands, PTCH, SMO and GLI, whereas the noncanonical HH pathway involves the activation of SMO or GLI through other pathways. The role of SMO has been discussed in different types of cancer, including breast, liver, pancreatic and colon cancers. SMO expression correlates with tumor size, invasiveness, metastasis and recurrence. In addition, SMO inhibitors can suppress cancer formation, reduce the proliferation of cancer cells, trigger apoptosis and suppress cancer stem cell activity. A better understanding of the role of SMO in cancer could contribute to the development of novel therapeutic approaches.
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Khaliullina, Helena, Mesut Bilgin, Julio L. Sampaio, Andrej Shevchenko, and Suzanne Eaton. "Endocannabinoids are conserved inhibitors of the Hedgehog pathway." Proceedings of the National Academy of Sciences 112, no. 11 (March 2, 2015): 3415–20. http://dx.doi.org/10.1073/pnas.1416463112.
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Hedgehog ligands control tissue development and homeostasis by alleviating repression of Smoothened, a seven-pass transmembrane protein. The Hedgehog receptor, Patched, is thought to regulate the availability of small lipophilic Smoothened repressors whose identity is unknown. Lipoproteins contain lipids required to repress Smoothened signaling in vivo. Here, using biochemical fractionation and lipid mass spectrometry, we identify these repressors as endocannabinoids. Endocannabinoids circulate in human and Drosophila lipoproteins and act directly on Smoothened at physiological concentrations to repress signaling in Drosophila and mammalian assays. Phytocannabinoids are also potent Smo inhibitors. These findings link organismal metabolism to local Hedgehog signaling and suggest previously unsuspected mechanisms for the physiological activities of cannabinoids.
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Meloni, Alison R., Gregory B. Fralish, Patrick Kelly, Ali Salahpour, James K. Chen, Robert J. Wechsler-Reya, Robert J. Lefkowitz, and Marc G. Caron. "Smoothened Signal Transduction Is Promoted by G Protein-Coupled Receptor Kinase 2." Molecular and Cellular Biology 26, no. 20 (August 14, 2006): 7550–60. http://dx.doi.org/10.1128/mcb.00546-06.
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ABSTRACT Deregulation of the Sonic hedgehog pathway has been implicated in an increasing number of human cancers. In this pathway, the seven-transmembrane (7TM) signaling protein Smoothened regulates cellular proliferation and differentiation through activation of the transcription factor Gli. The activity of mammalian Smoothened is controlled by three different hedgehog proteins, Indian, Desert, and Sonic hedgehog, through their interaction with the Smoothened inhibitor Patched. However, the mechanisms of signal transduction from Smoothened are poorly understood. We show that a kinase which regulates signaling by many “conventional” 7TM G-protein-coupled receptors, G protein-coupled receptor kinase 2 (GRK2), participates in Smoothened signaling. Expression of GRK2, but not catalytically inactive GRK2, synergizes with active Smoothened to mediate Gli-dependent transcription. Moreover, knockdown of endogenous GRK2 by short hairpin RNA (shRNA) significantly reduces signaling in response to the Smoothened agonist SAG and also inhibits signaling induced by an oncogenic Smoothened mutant, Smo M2. We find that GRK2 promotes the association between active Smoothened and β-arrestin 2. Indeed, Gli-dependent signaling, mediated by coexpression of Smoothened and GRK2, is diminished by β-arrestin 2 knockdown with shRNA. Together, these data suggest that GRK2 plays a positive role in Smoothened signaling, at least in part, through the promotion of an association between β-arrestin 2 and Smoothened.
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Fan, Junwan, Zichen Zhao, Ru Liu, Haowen Li, Wenyan He, Jianping Wu, Yongjun Wang, and Wei Chen. "A Potent Antagonist of Smoothened in Hedgehog Signaling for Epilepsy." International Journal of Molecular Sciences 23, no. 23 (November 22, 2022): 14505. http://dx.doi.org/10.3390/ijms232314505.
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Epilepsy is one of the common encephalopathies caused by sudden abnormal discharges of neurons in the brain. About 30% of patients with epilepsy are insensitive and refractory to existing antiseizure medications. The sonic hedgehog signaling pathway is essential to the development and homeostasis of brain. Aberrant sonic hedgehog signaling is increased in refractory epileptic lesions and may involve the etiology of epilepsy. Thus, new inhibitors of Smoothened, a key signal transducer of this signaling pathway are urgently need for refractory epilepsy. We have established a high-throughput screening platform and discovered several active small molecules targeting Smoothened including TT22. Here we show that the novel Smoothened inhibitor TT22 could block the translocation of βarrestin2-GFP to Smoothened, reduce the accumulation of Smoothened on primary cilia, displace Bodipy-cyclopamine binding to Smoothened, and inhibit the expression of downstream Gli transcription factor. Moreover, TT22 inhibits the abnormal seizure-like activity in neurons. Furthermore, we demonstrated that FDA-approved Smoothened inhibitor GDC-0449 and LDE-225 are able to inhibit abnormal seizure-like activity in neurons. Thus, our study suggests that targeting the sonic hedgehog signaling with new small-molecule Smoothened inhibitors might provide a potential new therapeutic avenue for refractory epilepsy.
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Gonnissen, Annelies, Sofie Isebaert, and Karin Haustermans. "Targeting the Hedgehog signaling pathway in cancer: beyond Smoothened." Oncotarget 6, no. 16 (May 22, 2015): 13899–913. http://dx.doi.org/10.18632/oncotarget.4224.
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Pietrobono, Silvia, and Barbara Stecca. "Targeting the Oncoprotein Smoothened by Small Molecules: Focus on Novel Acylguanidine Derivatives as Potent Smoothened Inhibitors." Cells 7, no. 12 (December 14, 2018): 272. http://dx.doi.org/10.3390/cells7120272.
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Hedgehog-GLI (HH) signaling was originally identified as a critical morphogenetic pathway in embryonic development. Since its discovery, a multitude of studies have reported that HH signaling also plays key roles in a variety of cancer types and in maintaining tumor-initiating cells. Smoothened (SMO) is the main transducer of HH signaling, and in the last few years, it has emerged as a promising therapeutic target for anticancer therapy. Although vismodegib and sonidegib have demonstrated effectiveness for the treatment of basal cell carcinoma (BCC), their clinical use has been hampered by severe side effects, low selectivity against cancer stem cells, and the onset of mutation-driven drug resistance. Moreover, SMO antagonists are not effective in cancers where HH activation is due to mutations of pathway components downstream of SMO, or in the case of noncanonical, SMO-independent activation of the GLI transcription factors, the final mediators of HH signaling. Here, we review the current and rapidly expanding field of SMO small-molecule inhibitors in experimental and clinical settings, focusing on a class of acylguanidine derivatives. We also discuss various aspects of SMO, including mechanisms of resistance to SMO antagonists.
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Martorana, Margherita. "A formalization of one of the main claims of “Sonic hedgehog signaling in astrocytes” by Hill et al. 20211." Data Science 5, no. 1 (March 22, 2022): 35–37. http://dx.doi.org/10.3233/ds-210043.
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Hill et al. claimed in previous work that sonic hedgehog signalling pathway is an essential regulator of astrocytes development. We present here a formalization of that claim, stating that all things of class “smoothened signaling pathway” that are in the context of a thing of class “human” mostly have a relation of type “affects” to a thing of class “astrocyte development” in the same context.
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Shyamala, Baragur V., and Krishna Moorthi Bhat. "A positive role for Patched-Smoothened signaling in promoting cell proliferation during normal head development in Drosophila." Development 129, no. 8 (April 15, 2002): 1839–47. http://dx.doi.org/10.1242/dev.129.8.1839.
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The transmembrane receptor Patched regulates several developmental processes in both invertebrates and vertebrates. In vertebrates, Patched also acts as a tumor suppressor. The Patched pathway normally operates by negatively regulating Smoothened, a G-protein-coupled receptor; binding of Hedgehog ligand to Patched relieves this negative interaction and allows signaling by Smoothened. We show that Ptc regulates Drosophila head development by promoting cell proliferation in the eye-antennal disc. During head morphogenesis, Patched positively interacts with Smoothened, which leads to the activation of Activin type I receptor Baboon and stimulation of cell proliferation in the eye-antennal disc. Thus, loss of Ptc or Smoothened activity affects cell proliferation in the eye-antennal disc and results in adult head capsule defects. Similarly, reducing the dose of smoothened in a patched background enhances the head defects. Consistent with these results, gain-of-function Hedgehog interferes with the activation of Baboon by Patched and Smoothened, leading to a similar head capsule defect. Expression of an activated form of Baboon in the patched domain in a patched mutant background completely rescues the head defects. These results provide insight into head morphogenesis, a process we know very little about, and reveal an unexpected non-canonical positive signaling pathway in which Patched and Smoothened function to promote cell proliferation as opposed to repressing it.
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Petrov, Kostadin, Taciani de Almeida Magalhaes, and Adrian Salic. "Mechanism and ultrasensitivity in Hedgehog signaling revealed by Patched1 disease mutations." Proceedings of the National Academy of Sciences 118, no. 6 (February 1, 2021): e2006800118. http://dx.doi.org/10.1073/pnas.2006800118.
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Hedgehog signaling is fundamental in animal embryogenesis, and its dysregulation causes cancer and birth defects. The pathway is triggered when the Hedgehog ligand inhibits the Patched1 membrane receptor, relieving repression that Patched1 exerts on the GPCR-like protein Smoothened. While it is clear how loss-of-function Patched1 mutations cause hyperactive Hedgehog signaling and cancer, how other Patched1 mutations inhibit signaling remains unknown. Here, we develop quantitative single-cell functional assays for Patched1, which, together with mathematical modeling, indicate that Patched1 inhibits Smoothened enzymatically, operating in an ultrasensitive regime. Based on this analysis, we propose that Patched1 functions in cilia, catalyzing Smoothened deactivation by removing cholesterol bound to its extracellular, cysteine-rich domain. Patched1 mutants associated with holoprosencephaly dampen signaling by three mechanisms: reduced affinity for Hedgehog ligand, elevated catalytic activity, or elevated affinity for the Smoothened substrate. Our results clarify the enigmatic mechanism of Patched1 and explain how Patched1 mutations lead to birth defects.
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Zhang, Boyan, Tenghan Zhuang, Qiaoyu Lin, Biying Yang, Xiaowei Xu, Guangwei Xin, Shicong Zhu, et al. "Patched1–ArhGAP36–PKA–Inversin axis determines the ciliary translocation of Smoothened for Sonic Hedgehog pathway activation." Proceedings of the National Academy of Sciences 116, no. 3 (December 31, 2018): 874–79. http://dx.doi.org/10.1073/pnas.1804042116.
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The Sonic Hedgehog (Shh) pathway conducts primarily in the primary cilium and plays important roles in cell proliferation, individual development, and tumorigenesis. Shh ligand binding with its ciliary membrane-localized transmembrane receptor Patched1 results in the removal of Patched1 from and the translocation of the transmembrane oncoprotein Smoothened into the cilium, leading to Shh signaling activation. However, how these processes are coupled remains unknown. Here, we show that the Patched1–ArhGAP36–PKA–Inversin axis determines the ciliary translocation of Smoothened. We find that Patched1 interacts with and stabilizes the PKA negative regulator ArhGAP36 to the centrosome. Activating the Shh pathway results in the removal of ArhGAP36 from the mother centriole and the centrosomal PKA accumulation. This PKA then phosphorylates Inversin and promotes its interaction with and the ciliary translocation of Smoothened. Knockdown of Inversin disrupts the ciliary translocation of Smoothened and Shh pathway activation. These findings reveal a regulatory molecular mechanism for the initial step of Shh pathway activation.
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Myers, Benjamin R., Lila Neahring, Yunxiao Zhang, Kelsey J. Roberts, and Philip A. Beachy. "Rapid, direct activity assays for Smoothened reveal Hedgehog pathway regulation by membrane cholesterol and extracellular sodium." Proceedings of the National Academy of Sciences 114, no. 52 (December 11, 2017): E11141—E11150. http://dx.doi.org/10.1073/pnas.1717891115.
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Hedgehog signaling specifies tissue patterning and renewal, and pathway components are commonly mutated in certain malignancies. Although central to ensuring appropriate pathway activity in all Hedgehog-responsive cells, how the transporter-like receptor Patched1 regulates the seven-transmembrane protein Smoothened remains mysterious, partially due to limitations in existing tools and experimental systems. Here we employ direct, real-time, biochemical and physiology-based approaches to monitor Smoothened activity in cellular and in vitro contexts. Patched1–Smoothened coupling is rapid, dynamic, and can be recapitulated without cilium-specific proteins or lipids. By reconstituting purified Smoothened in vitro, we show that cholesterol within the bilayer is sufficient for constitutive Smoothened activation. Cholesterol effects occur independently of the lipid-binding Smoothened extracellular domain, a region that is dispensable for Patched1–Smoothened coupling. Finally, we show that Patched1 specifically requires extracellular Na+ to regulate Smoothened in our assays, raising the possibility that a Na+ gradient provides the energy source for Patched1 catalytic activity. Our work suggests a hypothesis wherein Patched1, chemiosmotically driven by the transmembrane Na+ gradient common to metazoans, regulates Smoothened by shielding its heptahelical domain from cholesterol, or by providing an inhibitor that overrides this cholesterol activation.
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Kiprilov, Enko N., Aashir Awan, Romain Desprat, Michelle Velho, Christian A. Clement, Anne Grete Byskov, Claus Y. Andersen, et al. "Human embryonic stem cells in culture possess primary cilia with hedgehog signaling machinery." Journal of Cell Biology 180, no. 5 (March 10, 2008): 897–904. http://dx.doi.org/10.1083/jcb.200706028.
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Human embryonic stem cells (hESCs) are potential therapeutic tools and models of human development. With a growing interest in primary cilia in signal transduction pathways that are crucial for embryological development and tissue differentiation and interest in mechanisms regulating human hESC differentiation, demonstrating the existence of primary cilia and the localization of signaling components in undifferentiated hESCs establishes a mechanistic basis for the regulation of hESC differentiation. Using electron microscopy (EM), immunofluorescence, and confocal microscopies, we show that primary cilia are present in three undifferentiated hESC lines. EM reveals the characteristic 9 + 0 axoneme. The number and length of cilia increase after serum starvation. Important components of the hedgehog (Hh) pathway, including smoothened, patched 1 (Ptc1), and Gli1 and 2, are present in the cilia. Stimulation of the pathway results in the concerted movement of Ptc1 out of, and smoothened into, the primary cilium as well as up-regulation of GLI1 and PTC1. These findings show that hESCs contain primary cilia associated with working Hh machinery.
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Chen, Wenbiao, Shawn Burgess, and Nancy Hopkins. "Analysis of the zebrafishsmoothenedmutant reveals conserved and divergent functions of hedgehog activity." Development 128, no. 12 (June 15, 2001): 2385–96. http://dx.doi.org/10.1242/dev.128.12.2385.
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Despite extensive studies, there are still many unanswered questions regarding the mechanism of hedgehog signaling and the phylogenic conservation of hedgehog function in vertebrates. For example, whether hedgehog signaling in vertebrates requires smoothened is unclear, and the role of hedgehog activity in zebrafish is controversial. We show that inactivation of smoothened by retroviral insertions in zebrafish results in defects that are characteristic of hedgehog deficiencies, including abnormalities in body size, the central nervous system, adaxial mesoderm, cartilage and pectoral fins. We demonstrate that, as in Drosophila, vertebrate smoothened is essential for hedgehog signaling, and functions upstream of protein kinase A. Further analysis of neural tube defects revealed the absence of lateral floor plate and secondary motoneurons, but the presence of medial floor plate and primary motoneurons in smoothened mutant embryos. Blocking maternal hedgehog signaling by cyclopamine eliminates primary motoneurons, but not medial floor plate. Interestingly, even after inhibition of maternal hedgehog activity, the midbrain dopaminergic neurons still form, and looping of the heart does not randomize in the mutants. We also found decreased proliferation and increased apoptosis in the mutants. Taken together, these data demonstrate the conserved role of vertebrate smoothened in the hedgehog signaling pathway, and reveal similarities and differences of hedgehog function between teleosts and amniotes.
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Abraham, Ajay, and William Matsui. "Hedgehog Signaling in Myeloid Malignancies." Cancers 13, no. 19 (September 29, 2021): 4888. http://dx.doi.org/10.3390/cancers13194888.
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Myeloid malignancies arise from normal hematopoiesis and include several individual disorders with a wide range of clinical manifestations, treatment options, and clinical outcomes. The Hedgehog (HH) signaling pathway is aberrantly activated in many of these diseases, and glasdegib, a Smoothened (SMO) antagonist and HH pathway inhibitor, has recently been approved for the treatment of acute myeloid leukemia (AML). The efficacy of SMO inhibitors in AML suggests that they may be broadly active, but clinical studies in other myeloid malignancies have been largely inconclusive. We will discuss the biological role of the HH pathway in normal hematopoiesis and myeloid malignancies and review clinical studies targeting HH signaling in these diseases. In addition, we will examine SMO-independent pathway activation and highlight potential strategies that may expand the clinical utility of HH pathway antagonists.
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Chai, Jian Yi, Vaisnevee Sugumar, Mohammed Abdullah Alshawsh, Won Fen Wong, Aditya Arya, Pei Pei Chong, and Chung Yeng Looi. "The Role of Smoothened-Dependent and -Independent Hedgehog Signaling Pathway in Tumorigenesis." Biomedicines 9, no. 9 (September 10, 2021): 1188. http://dx.doi.org/10.3390/biomedicines9091188.
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The Hedgehog (Hh)-glioma-associated oncogene homolog (GLI) signaling pathway is highly conserved among mammals, with crucial roles in regulating embryonic development as well as in cancer initiation and progression. The GLI transcription factors (GLI1, GLI2, and GLI3) are effectors of the Hh pathway and are regulated via Smoothened (SMO)-dependent and SMO-independent mechanisms. The SMO-dependent route involves the common Hh-PTCH-SMO axis, and mutations or transcriptional and epigenetic dysregulation at these levels lead to the constitutive activation of GLI transcription factors. Conversely, the SMO-independent route involves the SMO bypass regulation of GLI transcription factors by external signaling pathways and their interacting proteins or by epigenetic and transcriptional regulation of GLI transcription factors expression. Both routes of GLI activation, when dysregulated, have been heavily implicated in tumorigenesis of many known cancers, making them important targets for cancer treatment. Hence, this review describes the various SMO-dependent and SMO-independent routes of GLI regulation in the tumorigenesis of multiple cancers in order to provide a holistic view of the paradigms of hedgehog signaling networks involving GLI regulation. An in-depth understanding of the complex interplay between GLI and various signaling elements could help inspire new therapeutic breakthroughs for the treatment of Hh-GLI-dependent cancers in the future. Lastly, we have presented an up-to-date summary of the latest findings concerning the use of Hh inhibitors in clinical developmental studies and discussed the challenges, perspectives, and possible directions regarding the use of SMO/GLI inhibitors in clinical settings.
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Terao, Toshiki, and Yosuke Minami. "Targeting Hedgehog (Hh) Pathway for the Acute Myeloid Leukemia Treatment." Cells 8, no. 4 (April 3, 2019): 312. http://dx.doi.org/10.3390/cells8040312.
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The Hedgehog (Hh) pathway, containing the Patched (PTCH) and Smoothened (SMO) multitransmembrane proteins, is the main regulator of vertebrate embryonic development. A non-canonical Hh pathway was recently observed in numerous types of solid cancers and hematological malignancies. Although acute myeloid leukemia (AML) is a common and lethal myeloid malignancy, the chemotherapy for AML has not changed in the last three decades. The Hh pathway and other intracellular signaling pathways are important for the tumor cells’ cycle or therapeutic resistance of AML cells. In this article, we will review the current trends in Hh pathway inhibitors for treating AML.
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Jeng, Kuo-Shyang, Chiung-Fang Chang, and Shu-Sheng Lin. "Sonic Hedgehog Signaling in Organogenesis, Tumors, and Tumor Microenvironments." International Journal of Molecular Sciences 21, no. 3 (January 23, 2020): 758. http://dx.doi.org/10.3390/ijms21030758.
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During mammalian embryonic development, primary cilia transduce and regulate several signaling pathways. Among the various pathways, Sonic hedgehog (SHH) is one of the most significant. SHH signaling remains quiescent in adult mammalian tissues. However, in multiple adult tissues, it becomes active during differentiation, proliferation, and maintenance. Moreover, aberrant activation of SHH signaling occurs in cancers of the skin, brain, liver, gallbladder, pancreas, stomach, colon, breast, lung, prostate, and hematological malignancies. Recent studies have shown that the tumor microenvironment or stroma could affect tumor development and metastasis. One hypothesis has been proposed, claiming that the pancreatic epithelia secretes SHH that is essential in establishing and regulating the pancreatic tumor microenvironment in promoting cancer progression. The SHH signaling pathway is also activated in the cancer stem cells (CSC) of several neoplasms. The self-renewal of CSC is regulated by the SHH/Smoothened receptor (SMO)/Glioma-associated oncogene homolog I (GLI) signaling pathway. Combined use of SHH signaling inhibitors and chemotherapy/radiation therapy/immunotherapy is therefore key in targeting CSCs.
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Ma, Guoqiang, Shuang Li, Yuhong Han, Shuangxi Li, Tao Yue, Bing Wang, and Jin Jiang. "Regulation of Smoothened Trafficking and Hedgehog Signaling by the SUMO Pathway." Developmental Cell 39, no. 4 (November 2016): 438–51. http://dx.doi.org/10.1016/j.devcel.2016.09.014.
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Lou, Hong, Hongchuan Li, Andrew R. Huehn, Nadya I. Tarasova, Bahara Saleh, Stephen K. Anderson, and Michael Dean. "Genetic and Epigenetic Regulation of the Smoothened Gene (SMO) in Cancer Cells." Cancers 12, no. 8 (August 8, 2020): 2219. http://dx.doi.org/10.3390/cancers12082219.
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(1) Background: The hedgehog (HH) signaling pathway is a key regulator of embryonic patterning, tissue regeneration, stem cell renewal, and cancer growth. The smoothened (SMO) protein regulates the HH signaling pathway and has demonstrated oncogenic activity. (2) Methods: To clarify the role of the HH signaling pathway in tumorigenesis, the expression profile of key HH signaling molecules, including SMO, PTCH1, GLI1, GLI2, and GLI3, were determined in 33 cancer cell lines and normal prostate cells and tissues. We performed a computational analysis of the upstream region of the SMO gene to identify the regulatory elements. (3) Results: Three potential CpG islands and several putative SMO promoter elements were identified. Luciferase reporter assays mapped key SMO promoter elements, and functional binding sites for SP1, AP1, CREB, and AP-2α transcription factors in the core SMO promoter region were confirmed. A hypermethylated SMO promoter was identified in several cancer cell lines suggesting an important role for epigenetic silencing of SMO expression in certain cancer cells. (4) Discussion: These results have important implications for our understanding of regulatory mechanisms controlling HH pathway activity and the molecular basis of SMO gene function. Moreover, this study may prove valuable for future research aimed at producing therapeutic downregulation of SMO expression in cancer cells.
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Milenkovic, Ljiljana, Matthew P. Scott, and Rajat Rohatgi. "Lateral transport of Smoothened from the plasma membrane to the membrane of the cilium." Journal of Cell Biology 187, no. 3 (October 26, 2009): 365–74. http://dx.doi.org/10.1083/jcb.200907126.
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The function of primary cilia depends critically on the localization of specific proteins in the ciliary membrane. A major challenge in the field is to understand protein trafficking to cilia. The Hedgehog (Hh) pathway protein Smoothened (Smo), a 7-pass transmembrane protein, moves to cilia when a ligand is received. Using microscopy-based pulse-chase analysis, we find that Smo moves through a lateral transport pathway from the plasma membrane to the ciliary membrane. Lateral movement, either via diffusion or active transport, is quite distinct from currently studied pathways of ciliary protein transport in mammals, which emphasize directed trafficking of Golgi-derived vesicles to the base of the cilium. We anticipate that this alternative route will be used by other signaling proteins that function at cilia. The path taken by Smo may allow novel strategies for modulation of Hh signaling in cancer and regeneration.
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Merchant, Akil A., Giselle A. Joseph, Evan Jones, Tara Lin, B. Doug Smith, Micheal McDevitt, Judith E. Karp, Craig Peacock, David N. Watkins, and William H. Matsui. "Hedgehog Signaling in Normal and Malignant Hematopoiesis." Blood 110, no. 11 (November 16, 2007): 3381. http://dx.doi.org/10.1182/blood.v110.11.3381.3381.
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Abstract The Hedgehog (Hh) signaling pathway is critical for normal development and dictates the self-renewal, proliferation and differentiation of normal stem cells and progenitors. Aberrant reactivation of Hh signaling has been described in a wide variety of human cancers and its role in normal stem cells suggest that pathway dysregulation contributes to oncogenesis and influences the cell fate decisions in cancer stem cells (CSC). Like their normal counterparts, CSC appear to undergo self-renewal as well as give rise to differentiated progeny, and these properties implicate that CSC are responsible for continual tumor cell production that underlies the initiation, maintenance and progression of clinical disease. Myeloid leukemias have long served as the model system for human CSC, but the cellular processes responsible for regulating these rare biologically distinct cell populations have remained unclear. We hypothesized that Hh pathway activation contributes to the pathogenesis of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) and studied Hh signaling in these settings. Using both RT-PCR for pathway components and a Gli1 reporter assay, we have found that Hh signaling is active in several human AML derived cell lines (Kasumi-1, KG1, KG1a) and primary AML and MDS samples. Approximately 80% (19/24) of primary AML samples tested express the downstream effectors GLI1 or GLI2 indicative of active Hh signaling. Furthermore, inhibition of Hh signaling with the naturally derived SMOOTHENED antagonist cyclopamine reduces the clonogenic growth of KG1 cells implicating the pathway in self-renewal. In contrast, cyclopamine failed to affect colony growth in the HL-60 cell line that lacks expression of Hh pathway signaling components, confirming that the effect of Hh inhibition is specific. In addition, the ectopic expression of Gli1 in KG1 cells partially rescued the effect of cyclopamine on colony formation further demonstrating the specific nature of this compound. We also studied normal CD34+ bone marrow cells and found that they expressed components of Hh pathway by RT-PCR. However, in contrast to KG1 cells, cyclopamine had little effect on the recovery of either normal hematopoietic progenitors or stem cells in an in vitro long-term culture assay. Therefore, it appears that Hh inhibition may preferentially inhibit myeloid leukemias. We further studied the role of Hh pathway activation on normal hematopoiesis and developed a transgenic mouse model in which SMOOTHENED is conditionally over-expressed in the myeloid lineage via Cre recombinase activity regulated by the Lysozyme promoter. Analysis of these mice demonstrated only subtle changes in peripheral blood counts, but further analysis of cells expressing the transgene revealed a significant reduction in the number of mature myeloid cells. This was confirmed by analyzing blood cells for the granulocyte marker Gr1 and pan-myeloid marker Mac1, both of which were significantly reduced in the SMOOTHENED over-expressing cells. These defects are reminiscent of MDS and further suggest that the Hh signaling pathway plays a role in normal hematopoiesis. Therefore, aberrant Hh pathway activation is a feature of myeloid leukemias and inhibitors such as cyclopamine may have a therapeutic role in the treatment of AML and MDS.
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Xie, Hao, Brooke D. Paradise, Wen Wee Ma, and Martin E. Fernandez-Zapico. "Recent Advances in the Clinical Targeting of Hedgehog/GLI Signaling in Cancer." Cells 8, no. 5 (April 29, 2019): 394. http://dx.doi.org/10.3390/cells8050394.
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The Hedgehog/GLI signaling pathway plays an important role in normal embryonic tissue development and has been implicated in the pathogenesis of various human cancers. In this review article, we summarize pre-clinical evidence supporting the suitability of targeting this signaling pathway in cancers. We review agents blocking both the ligand-dependent and ligand-independent cascades, and discuss the clinical evidence, which has led to the FDA approval of Hedgehog receptor Smoothened inhibitors, vismodegib, and sonidegib, in different malignancies. Finally, we provide an overview of published and ongoing clinical trial data on single agent or combination therapeutic strategies, targeting Hedgehog/GLI signaling pathway, in both advanced solid tumors and hematologic malignancies.
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Rimkus, Tadas, Richard Carpenter, Shadi Qasem, Michael Chan, and Hui-Wen Lo. "Targeting the Sonic Hedgehog Signaling Pathway: Review of Smoothened and GLI Inhibitors." Cancers 8, no. 2 (February 15, 2016): 22. http://dx.doi.org/10.3390/cancers8020022.
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Sever, Navdar, Randall K. Mann, Libin Xu, William J. Snell, Carmen I. Hernandez-Lara, Ned A. Porter, and Philip A. Beachy. "Endogenous B-ring oxysterols inhibit the Hedgehog component Smoothened in a manner distinct from cyclopamine or side-chain oxysterols." Proceedings of the National Academy of Sciences 113, no. 21 (May 9, 2016): 5904–9. http://dx.doi.org/10.1073/pnas.1604984113.
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Cellular lipids are speculated to act as key intermediates in Hedgehog signal transduction, but their precise identity and function remain enigmatic. In an effort to identify such lipids, we pursued a Hedgehog pathway inhibitory activity that is particularly abundant in flagellar lipids of Chlamydomonas reinhardtii, resulting in the purification and identification of ergosterol endoperoxide, a B-ring oxysterol. A mammalian analog of ergosterol, 7-dehydrocholesterol (7-DHC), accumulates in Smith–Lemli–Opitz syndrome, a human genetic disease that phenocopies deficient Hedgehog signaling and is caused by genetic loss of 7-DHC reductase. We found that depleting endogenous 7-DHC with methyl-β-cyclodextrin treatment enhances Hedgehog activation by a pathway agonist. Conversely, exogenous addition of 3β,5α-dihydroxycholest-7-en-6-one, a naturally occurring B-ring oxysterol derived from 7-DHC that also accumulates in Smith–Lemli–Opitz syndrome, blocked Hedgehog signaling by inhibiting activation of the essential transduction component Smoothened, through a mechanism distinct from Smoothened modulation by other lipids.
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Takada, Tomoaki. "Activation of the Hedgehog and Wnt/β-Catenin Signaling Pathways in Basal Cell Carcinoma." Case Reports in Dermatology 13, no. 3 (November 16, 2021): 506–12. http://dx.doi.org/10.1159/000520256.
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In basal cell carcinoma (BCC) tumorigenesis, interaction between Hedgehog (Hh) and Wnt/β-catenin (Wnt) signaling pathways has been investigated, but not completely elucidated. Here, a case of sporadic BCC in an 80-year-old man is presented, and the effectiveness of SMO inhibitors in case of relapse is predicted. The aim of this study was to determine whether the SMO inhibitors can be effective in treating this individual should the tumor recur in the future. Immunohistochemistry (IHC) was performed in a tumor and the adjacent skin tissue from the patient. IHC within the same BCC tissue specimen revealed that Glioma-associated oncogene 1 (GLI1) and Smoothened (SMO) in the Hh signaling pathway and insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) in the Wnt signaling pathway were overexpressed. Hh and Wnt signaling pathways were activated. These findings suggest that the patient might be resistant to treatment with SMO inhibitors because of the interaction between Hh and Wnt signaling pathways. Overexpression of GLI1 leads to transcriptional activation, making it an attractive molecular target for anticancer therapy owing to the downstream effectors of the cascade.
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Khera, Himanshi, Anupam Awasthi, and Sidharth Mehan. "Sonic Hedgehog Signaling Activation Promotes Cardioprotective Strategies." Current Signal Transduction Therapy 15, no. 2 (December 1, 2020): 197–204. http://dx.doi.org/10.2174/1574362413666181113124958.
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Background: Hedgehog pathway plays a crucial role in the neovascularisation and angiogenesis during the embryonic stage in humans. Three genes of hedgehog protein isolated from humans are Sonic hedgehog, Desert hedgehog and Indian hedgehog gene. Two G-protein coupled receptors identified in the sonic hedgehog pathway served as patched receptor and smoothened receptor. Materials and Methods: Particularly, sonic hedgehog gene plays a versatile role in cellular homeostasis and can be a novel therapeutic target in the prevention of cardiovascular disorders. Further various sonic hedgehog modulators have been reported working as futuristic drug molecules in the modulation of cardiovascular dysfunctions. Results: However, there was limited literature availability that has summarized the possible mechanism of targeting Sonic hedgehog signaling pathway. Conclusion: Thus, the present review is aimed at exploring the role of targeting sonic hedgehog protein signaling and modulators as well as to enlighten that how targeting sonic hedgehog protein involves in the amelioration of atherosclerosis, ischemic heart diseases, vascular endothelial dysfunction, heart failure and congenital heart diseases.
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Pal, Kasturi, Sun-hee Hwang, Bandarigoda Somatilaka, Hemant Badgandi, Peter K. Jackson, Kathryn DeFea, and Saikat Mukhopadhyay. "Smoothened determines β-arrestin–mediated removal of the G protein–coupled receptor Gpr161 from the primary cilium." Journal of Cell Biology 212, no. 7 (March 21, 2016): 861–75. http://dx.doi.org/10.1083/jcb.201506132.
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Dynamic changes in membrane protein composition of the primary cilium are central to development and homeostasis, but we know little about mechanisms regulating membrane protein flux. Stimulation of the sonic hedgehog (Shh) pathway in vertebrates results in accumulation and activation of the effector Smoothened within cilia and concomitant disappearance of a negative regulator, the orphan G protein–coupled receptor (GPCR), Gpr161. Here, we describe a two-step process determining removal of Gpr161 from cilia. The first step involves β-arrestin recruitment by the signaling competent receptor, which is facilitated by the GPCR kinase Grk2. An essential factor here is the ciliary trafficking and activation of Smoothened, which by increasing Gpr161–β-arrestin binding promotes Gpr161 removal, both during resting conditions and upon Shh pathway activation. The second step involves clathrin-mediated endocytosis, which functions outside of the ciliary compartment in coordinating Gpr161 removal. Mechanisms determining dynamic compartmentalization of Gpr161 in cilia define a new paradigm for down-regulation of GPCRs during developmental signaling from a specialized subcellular compartment.
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Ko, Yu-Chan, Hack Sun Choi, Ren Liu, and Dong-Sun Lee. "Physalin A, 13,14-Seco-16, 24-Cyclo-Steroid, Inhibits Stemness of Breast Cancer Cells by Regulation of Hedgehog Signaling Pathway and Yes-Associated Protein 1 (YAP1)." International Journal of Molecular Sciences 22, no. 16 (August 13, 2021): 8718. http://dx.doi.org/10.3390/ijms22168718.
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The Hedgehog (HH) signaling pathway plays an important role in embryonic development and adult organ homeostasis. Aberrant activity of the Hedgehog signaling pathway induces many developmental disorders and cancers. Recent studies have investigated the relationship of this pathway with various cancers. GPCR-like protein Smoothened (SMO) and the glioma-associated oncogene (GLI1) are the main effectors of Hedgehog signaling. Physalin A, a bioactive substance derived from Physalis alkekengi, inhibits proliferation and migration of breast cancer cells and mammospheres formation. Physalin A-induced apoptosis and growth inhibition of mammospheres, and reduced transcripts of cancer stem cell (CSC) marker genes. Physalin A reduced protein expressions of SMO and GLI1/2. Down-regulation of SMO and GLI1 using siRNA inhibited mammosphere formation. Physalin A reduced mammosphere formation by reducing GLI1 gene expression. Down-regulation of GLI1 reduced CSC marker genes. Physalin A reduced protein level of YAP1. Down-regulation of YAP1 using siRNA inhibited mammosphere formation. Physalin A reduced mammosphere formation through reduction of YAP1 gene expression. Down-regulation of YAP1 reduced CSC marker genes. We showed that treatment of MDA-MB-231 breast cancer cells with GLI1 siRNA induced inhibition of mammosphere formation and down-regulation of YAP1, a Hippo pathway effector. These results show that Hippo signaling is regulated by the Hedgehog signaling pathway. Physalin A also inhibits the canonical Hedgehog and Hippo signaling pathways, CSC-specific genes, and the formation of mammospheres. These findings suggest that physalin A is a potential therapeutic agent for targeting CSCs.
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Palla, Marco, Luigi Scarpato, Rossella Di Trolio, and Paolo Antonio Ascierto. "Sonic hedgehog pathway for the treatment of inflammatory diseases: implications and opportunities for future research." Journal for ImmunoTherapy of Cancer 10, no. 6 (June 2022): e004397. http://dx.doi.org/10.1136/jitc-2021-004397.
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The Sonic hedgehog (Shh) signaling pathway is an essential pathway in the human body that plays an important role in embryogenesis and tissue homeostasis. Aberrant activation of this pathway has been linked to the development of different diseases, ranging from cancer to immune dysregulation and infections.Uncontrolled activation of the pathway through sporadic mutations or other mechanisms is associated with cancer development and progression in various malignancies, such as basal cell carcinoma, medulloblastoma, pancreatic cancer, breast cancer and small-cell lung carcinoma. Targeted inhibition of the pathway components has therefore emerged as an attractive and validated therapeutic strategy for the treatment of a wide range of cancers. Currently, two main components of the pathway, the smoothened receptor and the glioma-associated oncogene homolog transcriptional factors, have been investigated for the development of targeted drugs, leading to the marketing authorization of three smoothened receptor inhibitors for the treatment of basal cell carcinoma and acute myeloid leukemia.The Shh pathway also seems to be involved in regulating the immune response, possibly playing a role in immune system evasions by tumors, development of autoimmune diseases, such as rheumatoid arthritis and Crohn’s disease, airway inflammation, and diseases related to aberrant activation of T-helper 2 cellular response, such as allergy, atopic dermatitis, and asthma.Finally, the Shh pathway is involved in pathogen-mediated infection, including influenza-A and, more recently, SARS-CoV-2 viruses. Therefore, agents that inhibit the Shh signaling pathway might be used to treat pathogenic infections, shifting the therapeutic approach from strain-specific treatments to host-based strategies that target highly conserved host targets.
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Siggins, Sarah L., Nhu-Y. N. Nguyen, Matthew P. McCormack, Sumitha Vasudevan, Rehan Villani, Stephen M. Jane, Brandon J. Wainwright, and David J. Curtis. "The Hedgehog receptor Patched1 regulates myeloid and lymphoid progenitors by distinct cell-extrinsic mechanisms." Blood 114, no. 5 (July 30, 2009): 995–1004. http://dx.doi.org/10.1182/blood-2009-03-208330.
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Hedgehog (Hh) ligands bind to the Patched1 (Ptch1) receptor, relieving repression of Smoothened, which leads to activation of the Hh signaling pathway. Using conditional Ptch1 knockout mice, the aim of this study was to determine the effects of activating the Hh signaling pathway in hematopoiesis. Surprisingly, hematopoietic-specific deletion of Ptch1 did not lead to activation of the Hh signaling pathway and, consequently, had no phenotypic effect. In contrast, deletion of Ptch1 in nonhematopoietic cells produced 2 distinct hematopoietic phenotypes. First, activation of Hh signaling in epithelial cells led to apoptosis of lymphoid progenitors associated with markedly elevated levels of circulating thymic stromal lymphopoietin. Second, activation of Hh signaling in the bone marrow cell niche led to increased numbers of lineage-negative c-kit+ Sca-1+ bone marrow cells and mobilization of myeloid progenitors associated with a marked loss of osteoblasts. Thus, deletion of Ptch1 leads to hematopoietic effects by distinct cell-extrinsic mechanisms rather than by direct activation of the Hh signaling pathway in hematopoietic cells. These findings have important implications for therapeutics designed to activate the Hh signaling pathway in hematopoietic cells including hematopoietic stem cells.
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Low, Jennifer A., and Frederic J. de Sauvage. "Clinical Experience With Hedgehog Pathway Inhibitors." Journal of Clinical Oncology 28, no. 36 (December 20, 2010): 5321–26. http://dx.doi.org/10.1200/jco.2010.27.9943.
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The Hedgehog (Hh) signaling pathway is critical for cell growth and differentiation during embryogenesis and early development. While it is mostly quiescent in adults, inappropriate reactivation of the Hh pathway has been shown to be involved in the development of cancer. A number of tumor types rely on overexpression of Hh ligands to activate the pathway in a paracrine manner from the tumor to the surrounding stroma. Alternatively, Hh ligands may act on cancer stem cells in some hematopoietic cancers, such as chronic myelogenous leukemia. However, the role of the Hh pathway is best established in tumors, such as basal cell carcinoma and medulloblastoma, where the pathway is activated via mutations. Understanding the contribution of Hh signaling in these various tumor types will be critical to the development and use of agents targeting this pathway in the clinic. We review here the activity of clinical inhibitors of the Hh pathway, including GDC-0449, a small molecule inhibitor of Smoothened (SMO).
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Drummond, Michael L., Mischa Li, Eric Tarapore, Tuyen T. L. Nguyen, Baina J. Barouni, Shaun Cruz, Kevin C. Tan, Anthony E. Oro, and Scott X. Atwood. "Actin polymerization controls cilia-mediated signaling." Journal of Cell Biology 217, no. 9 (June 26, 2018): 3255–66. http://dx.doi.org/10.1083/jcb.201703196.
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Primary cilia are polarized organelles that allow detection of extracellular signals such as Hedgehog (Hh). How the cytoskeleton supporting the cilium generates and maintains a structure that finely tunes cellular response remains unclear. Here, we find that regulation of actin polymerization controls primary cilia and Hh signaling. Disrupting actin polymerization, or knockdown of N-WASp/Arp3, increases ciliation frequency, axoneme length, and Hh signaling. Cdc42, a potent actin regulator, recruits both atypical protein pinase C iota/lambda (aPKC) and Missing-in-Metastasis (MIM) to the basal body to maintain actin polymerization and restrict axoneme length. Transcriptome analysis implicates the Src pathway as a major aPKC effector. aPKC promotes whereas MIM antagonizes Src activity to maintain proper levels of primary cilia, actin polymerization, and Hh signaling. Hh pathway activation requires Smoothened-, Gli-, and Gli1-specific activation by aPKC. Surprisingly, longer axonemes can amplify Hh signaling, except when aPKC is disrupted, reinforcing the importance of the Cdc42–aPKC–Gli axis in actin-dependent regulation of primary cilia signaling.
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Peer, Elisabeth, Suzana Tesanovic, and Fritz Aberger. "Next-Generation Hedgehog/GLI Pathway Inhibitors for Cancer Therapy." Cancers 11, no. 4 (April 15, 2019): 538. http://dx.doi.org/10.3390/cancers11040538.
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The Hedgehog/Glioma-associated oncogene homolog (HH/GLI) signaling pathway regulates self-renewal of rare and highly malignant cancer stem cells (CSC), which have been shown to account for the initiation and maintenance of tumor growth as well as for drug resistance, metastatic spread and relapse. Efficacious therapeutic approaches targeting CSC pathways, such as HH/GLI signaling in combination with chemo, radiation or immunotherapy are, therefore, of high medical need. Pharmacological inhibition of HH/GLI pathway activity represents a promising approach to eliminate malignant CSC. Clinically approved HH/GLI pathway inhibitors target the essential pathway effector Smoothened (SMO) with striking therapeutic efficacy in skin and brain cancer patients. However, multiple genetic and molecular mechanisms resulting in de novo and acquired resistance to SMO inhibitors pose major limitations to anti-HH/GLI therapies and, thus, the eradication of CSC. In this review, we summarize reasons for clinical failure of SMO inhibitors, including mechanisms caused by genetic alterations in HH pathway effectors or triggered by additional oncogenic signals activating GLI transcription factors in a noncanonical manner. We then discuss emerging novel and rationale-based approaches to overcome SMO-inhibitor resistance, focusing on pharmacological perturbations of enzymatic modifiers of GLI activity and on compounds either directly targeting oncogenic GLI factors or interfering with synergistic crosstalk signals known to boost the oncogenicity of HH/GLI signaling.
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Skoda, Ana Marija, Dora Simovic, Valentina Karin, Vedran Kardum, Semir Vranic, and Ljiljana Serman. "The role of the Hedgehog signaling pathway in cancer: A comprehensive review." Bosnian Journal of Basic Medical Sciences 18, no. 1 (February 20, 2018): 8–20. http://dx.doi.org/10.17305/bjbms.2018.2756.
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The Hedgehog (Hh) signaling pathway was first identified in the common fruit fly. It is a highly conserved evolutionary pathway of signal transmission from the cell membrane to the nucleus. The Hh signaling pathway plays an important role in the embryonic development. It exerts its biological effects through a signaling cascade that culminates in a change of balance between activator and repressor forms of glioma-associated oncogene (Gli) transcription factors. The components of the Hh signaling pathway involved in the signaling transfer to the Gli transcription factors include Hedgehog ligands (Sonic Hh [SHh], Indian Hh [IHh], and Desert Hh [DHh]), Patched receptor (Ptch1, Ptch2), Smoothened receptor (Smo), Suppressor of fused homolog (Sufu), kinesin protein Kif7, protein kinase A (PKA), and cyclic adenosine monophosphate (cAMP). The activator form of Gli travels to the nucleus and stimulates the transcription of the target genes by binding to their promoters. The main target genes of the Hh signaling pathway are PTCH1, PTCH2, and GLI1. Deregulation of the Hh signaling pathway is associated with developmental anomalies and cancer, including Gorlin syndrome, and sporadic cancers, such as basal cell carcinoma, medulloblastoma, pancreatic, breast, colon, ovarian, and small-cell lung carcinomas. The aberrant activation of the Hh signaling pathway is caused by mutations in the related genes (ligand-independent signaling) or by the excessive expression of the Hh signaling molecules (ligand-dependent signaling – autocrine or paracrine). Several Hh signaling pathway inhibitors, such as vismodegib and sonidegib, have been developed for cancer treatment. These drugs are regarded as promising cancer therapies, especially for patients with refractory/advanced cancers.
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Bhateja, Priyanka, Mathew Cherian, Sarmila Majumder, and Bhuvaneswari Ramaswamy. "The Hedgehog Signaling Pathway: A Viable Target in Breast Cancer?" Cancers 11, no. 8 (August 7, 2019): 1126. http://dx.doi.org/10.3390/cancers11081126.
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The hedgehog (Hh) pathway plays a key role in embryonic development and stem cell programs. Deregulation of the Hh pathway is a key driver of basal cell carcinoma, and therapeutic targeting led to approval of Hh inhibitor, vismodegib, in the management of this cancer. The Hh pathway is implicated in other malignancies including hormone receptor (HR+) positive and triple negative breast cancer (TNBC). Hh signaling, which is activated in human mammary stem cells, results in activation of glioma-associated oncogene (GLI) transcription factors. High GLI1 expression correlates with worse outcomes in breast cancer. Non-canonical GLI1 activation is one mechanism by which estrogen exposure promotes breast cancer stem cell proliferation and epithelial–mesenchymal transition. Tamoxifen resistant cell lines show aberrant activation of Hh signaling, and knockdown of Hh pathway inhibited growth of tamoxifen resistant cells. As in other cancers Hh signaling is activated by the PI3K/AKT pathway in these endocrine resistant cell lines. Hh pathway activation has also been reported to mediate chemotherapy resistance in TNBC via various mechanisms including paracrine signaling to tumor micro-environment and selective proliferation of cancer stem cells. Co-activation of Hh and Wnt signaling pathways is a poor prognostic marker in TNBC. Early phase clinical trials are evaluating the combination of smoothened (SMO) inhibitors and chemotherapy in TNBC. In addition to SMO inhibitors like vismodegib and sonidegib, which are in clinical use for basal cell carcinoma, GLI1 inhibitors like GANT58 and GANT61 are in preclinical drug development and might be an effective mechanism to overcome drug resistance in breast cancer. Gene signatures predictive of Hh pathway activation could enrich for patients likely to respond to these agents.
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Anichini, Giulia, Laura Carrassa, Barbara Stecca, Fabio Marra, and Chiara Raggi. "The Role of the Hedgehog Pathway in Cholangiocarcinoma." Cancers 13, no. 19 (September 24, 2021): 4774. http://dx.doi.org/10.3390/cancers13194774.
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Cholangiocarcinoma (CCA) is a poorly treatable type of cancer and, along with hepatocellular carcinoma (HCC), is the predominant type of primitive liver cancer in adults. The lack of understanding of CCA biology has slowed down the identification of novel targets and the development of effective treatments. While tumors share some general characteristics, detailed knowledge of specific features is essential for the development of effectively tailored therapeutic approaches. The Hedgehog (HH) signaling cascade regulates stemness biology, embryonal development, tissue homeostasis, and cell proliferation and differentiation. Its aberrant activation has been associated with a variety of solid and hematological human malignancies. Several HH-inhibiting compounds have been indeed developed as potential anticancer agents in different types of tumors, with Smoothened and GLI inhibitors showing the most promising results. Beside its well-established function in other tumors, findings regarding the HH signaling in CCA are still controversial. Here we will give an overview of the most important clinical and molecular features of cholangiocarcinoma, and we will discuss the available evidence of the crosstalk between the HH signaling pathway and the cholangiocarcinoma cell biology.
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Giammona, Alessandro, Enrica Crivaro, and Barbara Stecca. "Emerging Roles of Hedgehog Signaling in Cancer Immunity." International Journal of Molecular Sciences 24, no. 2 (January 10, 2023): 1321. http://dx.doi.org/10.3390/ijms24021321.
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Hedgehog–GLI (HH) signaling plays an essential role in embryogenesis and tissue homeostasis. Aberrant activation of the pathway through mutations or other mechanisms is involved in the development and progression of numerous types of cancer, including basal cell carcinoma, medulloblastoma, melanoma, breast, prostate, hepatocellular and pancreatic carcinomas. Activation of HH signaling sustains proliferation, suppresses cell death signals, enhances invasion and metastasis, deregulates cellular metabolism and promotes angiogenesis and tumor inflammation. Targeted inhibition of the HH pathway has therefore emerged as an attractive therapeutic strategy for the treatment of a wide range of cancers. Currently, the Smoothened (SMO) receptor and the downstream GLI transcriptional factors have been investigated for the development of targeted drugs. Recent studies have revealed that the HH signaling is also involved in tumor immune evasion and poor responses to cancer immunotherapy. Here we focus on the effects of HH signaling on the major cellular components of the adaptive and innate immune systems, and we present recent discoveries elucidating how the immunosuppressive function of the HH pathway is engaged by cancer cells to prevent immune surveillance. In addition, we discuss the future prospect of therapeutic options combining the HH pathway and immune checkpoint inhibitors.
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QU, Changju, Amineh Vaghefi, Kranthi Kunkalla, Jennifer R. Chapman, Yadong Liu, Marzenna Blonska, Juan Pablo Alderuccio, et al. "Smoothened Stabilizes and Protects TRAF6 from Proteosomal Degradation: A Novel Non-Canonical Role of Smoothened with Implications in Lymphoma Biology." Blood 130, Suppl_1 (December 7, 2017): 646. http://dx.doi.org/10.1182/blood.v130.suppl_1.646.646.
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Abstract Tumor necrosis factor receptor-associated factor 6 (TRAF6), an (K63) E3-ligase, plays a crucial role in many biological processes and its activity is relevant in the biology of multiple cancers including diffuse large B cell lymphoma (DLBCL). Although molecules that trigger TRAF6 activation have been defined, those that stabilize TRAF6 levels and/or enhance TRAF6 function remain largely unclear. Previously, we found that activation of smoothened (SMO) with recombinant Hedgehog (Hh) ligand increased the binding between SMO with TRAF6, as well as TRAF6 protein levels (Blood 2013; 121:4718-28). In addition, transient overexpression of SMO resulted in increased K63-Ub of both TRAF6 and NEMO indicating stabilization of these proteins resulting in NF-kB activation. This is relevant, as more recently we found that TRAF6 amplifies pAKT signaling in DLBCL and that TRAF6 is the dominant E3 ligase for the K63-Ub of AKT in DLBCL. Moreover, TRAF6 recruitment to the cell membrane, and stabilization of its ubiquitination profile are facilitated by SMO. SMO is a member of the Frizzled-class G-protein-coupled receptor (GPCRs) and is traditionally known for its role as signal transducer in canonical Hedgehog (Hh) signaling. These observations prompted us to investigate whether the ability of SMO to increase TRAF6 levels is limited to ligand induced signaling, whether it contributes to chemoresistance in DLBCL cells, and whether SMO directly participates in controlling TRAF6 levels. To confirm the regulatory role of SMO in the TRAF6/AKT axis in DLBCL cells (HBL1 and HT) and further outline the nature of the underlying regulation, we measured the impact of activation of the Hh pathway with recombinant Shh ligand on TRAF6 levels, with and without SMO knockdown or recombinant SMO overexpression. Canonical Hh signaling results in the activation of the GLI1 transcription factor and the subsequent elevation of GLI1 mRNA levels is an established indicator of activation of the Hh pathway. However, neither SMO activation nor the knockdown of GLI1 had a significant impact on TRAF6 mRNA levels. These findings indicate that TRAF6 is not transcriptionally regulated by SMO signaling through GLI1 (canonical Hh signaling). In contrast, overexpression of SMO or siRNA knockdown of SMO resulted in an increase or decrease of TRAF6 protein levels, respectively. Consistent with the decrease of AKT activation (pAKT T308 and S473) after TRAF6 knockdown, the increase in TRAF6 levels that follows SMO overexpression resulted in an increase in the levels of AKT phosphorylation. Altogether, these observations suggest a post-translational regulation of TRAF6 by SMO. Indeed, stable knockdown of SMO dramatically reduces the half-life of TRAF6 in both HBL1 and HT cells in the presence of cyclohexamide. Furthermore, overexpression of SMO increases K63-Ub of both TRAF6 and AKT. In contrast, the SMO induced decrease in K48-Ub occurred only for TRAF6 but not for AKT. These data link the SMO-stimulated activation of TRAF6 to the enhancement of AKT signaling and protection of TRAF6 from proteasomal degradation. Mechanistically, we found that SMO, through its C-terminal tail, stabilizes TRAF6 and protects TRAF6 from proteosomal degradation, an effect mediated by ubiquitin-specific protease-8 (USP8). Importantly, this functional link between SMO and TRAF6 is reflected in DLBCL patient samples where high expression of both molecules correlates with poor prognosis. Resistance to DXR is a serious challenge in the treatment of DLBCL, and activated AKT is known to contribute to DXR resistance in multiple cancers including DLBCL. We evaluated whether SMO and TRAF6 support resistance to DXR in DLBCL cell lines. We exposed HT and HBL1 cells as well as their counterparts with stable knockdown of TRAF6 or SMO to DXR for 96hrs. Cell viability after exposure to DXR was determined by an Annexin V and PI staining assay. Silencing SMO or TRAF6 dramatically decreased cell survival after treatment with DXR. In summary, we report that SMO is needed to facilitate and maintain TRAF6-dependent elevated pAKT levels in DLBCL cell lines of germinal (GC) and non-GC subtypes, and that the SMO/TRAF6 axis contributes to DXR resistance in DLBCL. Our study reveals a novel and potential central cell survival signaling mechanism in which SMO stabilizes and protects TRAF6 from proteosomal degradation. Disclosures Lossos: Affimed: Research Funding.
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Nguyen, Ngoc Minh, and Jungsook Cho. "Hedgehog Pathway Inhibitors as Targeted Cancer Therapy and Strategies to Overcome Drug Resistance." International Journal of Molecular Sciences 23, no. 3 (February 3, 2022): 1733. http://dx.doi.org/10.3390/ijms23031733.
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Hedgehog (Hh) signaling is a highly conserved pathway that plays a vital role during embryonic development. Recently, uncontrolled activation of this pathway has been demonstrated in various types of cancer. Therefore, Hh pathway inhibitors have emerged as an important class of anti-cancer agents. Unfortunately, however, their reputation has been tarnished by the emergence of resistance during therapy, necessitating clarification of mechanisms underlying the drug resistance. In this review, we briefly overview canonical and non-canonical Hh pathways and their inhibitors as targeted cancer therapy. In addition, we summarize the mechanisms of resistance to Smoothened (SMO) inhibitors, including point mutations of the drug binding pocket or downstream molecules of SMO, and non-canonical mechanisms to reinforce Hh pathway output. A distinct mechanism involving loss of primary cilia is also described to maintain GLI activity in resistant tumors. Finally, we address the main strategies to circumvent the drug resistance. These strategies include the development of novel and potent inhibitors targeting different components of the canonical Hh pathway or signaling molecules of the non-canonical pathway. Further studies are necessary to avoid emerging resistance to Hh inhibitors and establish an optimal customized regimen with improved therapeutic efficacy to treat various types of cancer, including basal cell carcinoma.
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Walter, Kimberly, Noriyuki Omura, Seung-Mo Hong, Margaret Griffith, Audrey Vincent, Michael Borges, and Michael Goggins. "Overexpression of Smoothened Activates the Sonic Hedgehog Signaling Pathway in Pancreatic Cancer–Associated Fibroblasts." Clinical Cancer Research 16, no. 6 (March 14, 2010): 1781–89. http://dx.doi.org/10.1158/1078-0432.ccr-09-1913.
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Fan, Chih-Wei, Baozhi Chen, Irene Franco, Jianming Lu, Heping Shi, Shuguang Wei, Changguang Wang, et al. "The Hedgehog Pathway Effector Smoothened Exhibits Signaling Competency in the Absence of Ciliary Accumulation." Chemistry & Biology 21, no. 12 (December 2014): 1680–89. http://dx.doi.org/10.1016/j.chembiol.2014.10.013.
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Fan, Chih-Wei, Baozhi Chen, Irene Franco, Jianming Lu, Heping Shi, Shuguang Wei, Changguang Wang, et al. "The Hedgehog Pathway Effector Smoothened Exhibits Signaling Competency in the Absence of Ciliary Accumulation." Chemistry & Biology 22, no. 4 (April 2015): 559. http://dx.doi.org/10.1016/j.chembiol.2015.04.001.
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Doheny, Daniel, Sara G. Manore, Grace L. Wong, and Hui-Wen Lo. "Hedgehog Signaling and Truncated GLI1 in Cancer." Cells 9, no. 9 (September 17, 2020): 2114. http://dx.doi.org/10.3390/cells9092114.
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The hedgehog (HH) signaling pathway regulates normal cell growth and differentiation. As a consequence of improper control, aberrant HH signaling results in tumorigenesis and supports aggressive phenotypes of human cancers, such as neoplastic transformation, tumor progression, metastasis, and drug resistance. Canonical activation of HH signaling occurs through binding of HH ligands to the transmembrane receptor Patched 1 (PTCH1), which derepresses the transmembrane G protein-coupled receptor Smoothened (SMO). Consequently, the glioma-associated oncogene homolog 1 (GLI1) zinc-finger transcription factors, the terminal effectors of the HH pathway, are released from suppressor of fused (SUFU)-mediated cytoplasmic sequestration, permitting nuclear translocation and activation of target genes. Aberrant activation of this pathway has been implicated in several cancer types, including medulloblastoma, rhabdomyosarcoma, basal cell carcinoma, glioblastoma, and cancers of lung, colon, stomach, pancreas, ovarian, and breast. Therefore, several components of the HH pathway are under investigation for targeted cancer therapy, particularly GLI1 and SMO. GLI1 transcripts are reported to undergo alternative splicing to produce truncated variants: loss-of-function GLI1ΔN and gain-of-function truncated GLI1 (tGLI1). This review covers the biochemical steps necessary for propagation of the HH activating signal and the involvement of aberrant HH signaling in human cancers, with a highlight on the tumor-specific gain-of-function tGLI1 isoform.
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Montagnani, Valentina, and Barbara Stecca. "Role of Protein Kinases in Hedgehog Pathway Control and Implications for Cancer Therapy." Cancers 11, no. 4 (March 29, 2019): 449. http://dx.doi.org/10.3390/cancers11040449.
Full textAbstract:
Hedgehog (HH) signaling is an evolutionarily conserved pathway that is crucial for growth and tissue patterning during embryonic development. It is mostly quiescent in the adult, where it regulates tissue homeostasis and stem cell behavior. Aberrant reactivation of HH signaling has been associated to several types of cancer, including those in the skin, brain, prostate, breast and hematological malignancies. Activation of the canonical HH signaling is triggered by binding of HH ligand to the twelve-transmembrane protein PATCHED. The binding releases the inhibition of the seven-transmembrane protein SMOOTHENED (SMO), leading to its phosphorylation and activation. Hence, SMO activates the transcriptional effectors of the HH signaling, that belong to the GLI family of transcription factors, acting through a not completely elucidated intracellular signaling cascade. Work from the last few years has shown that protein kinases phosphorylate several core components of the HH signaling, including SMO and the three GLI proteins, acting as powerful regulatory mechanisms to fine tune HH signaling activities. In this review, we will focus on the mechanistic influence of protein kinases on HH signaling transduction. We will also discuss the functional consequences of this regulation and the possible implications for cancer therapy.
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Eguether, Thibaut, Fabrice P. Cordelieres, and Gregory J. Pazour. "Intraflagellar transport is deeply integrated in hedgehog signaling." Molecular Biology of the Cell 29, no. 10 (May 15, 2018): 1178–89. http://dx.doi.org/10.1091/mbc.e17-10-0600.
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The vertebrate hedgehog pathway is organized in primary cilia, and hedgehog components relocate into or out of cilia during signaling. Defects in intraflagellar transport (IFT) typically disrupt ciliary assembly and attenuate hedgehog signaling. Determining whether IFT drives the movement of hedgehog components is difficult due to the requirement of IFT for building cilia. Unlike most IFT proteins, IFT27 is dispensable for cilia formation but affects hedgehog signaling similarly to other IFTs, allowing us to examine its role in the dynamics of signaling. Activating signaling at points along the pathway in Ift27 mutant cells showed that IFT is extensively involved in the pathway. Similar analysis of Bbs mutant cells showed that BBS proteins participate at many levels of signaling but are not needed to concentrate Gli transcription factors at the ciliary tip. Our analysis showed that smoothened delivery to cilia does not require IFT27, but the role of other IFTs is not known. Using a rapamycin-induced dimerization system to sequester IFT-B proteins at the mitochondria in cells with fully formed cilia did not affect the delivery of Smo to cilia, suggesting that this membrane protein may not require IFT-B for delivery.
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Daggubati, Vikas, Jordan Hochstelter, Ani Bommireddy, Abrar Choudhury, Alexis Krup, Pervinder Kaur, Pakteema Tong, et al. "DDRE-02. SMOOTHENED-ACTIVATING LIPIDS DRIVE RESISTANCE TO CDK4/6 INHIBITION IN HEDGEHOG-ASSOCIATED MEDULLOBLASTOMA." Neuro-Oncology Advances 3, Supplement_1 (March 1, 2021): i6. http://dx.doi.org/10.1093/noajnl/vdab024.024.
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Abstract BACKGROUND Medulloblastoma is an aggressive pediatric brain tumor that is associated with misactivation of the Hedgehog (HH) pathway. Our lab has shown that CDK6, a critical activator of the cell cycle, is a direct transcriptional target of oncogenic HH signaling, and that inhibiting CDK6 blocks the growth of HH-associated medulloblastoma in mice. A clinical trial exploring the efficacy of CDK6 inhibition in medulloblastoma patients is underway, but prior attempts to target the HH pathway in medulloblastoma have been encumbered by resistance to molecular monotherapy. Thus, we sought to identify mechanisms of resistance to CDK6 inhibition in HH-associated medulloblastoma. METHODS We performed orthogonal CRISPR and CRISPR interference screens in HH-associated medulloblastoma cells treated with pharmacologic inhibitors of CDK6 in vitro, and RNA-sequencing of HH-associated medulloblastomas with genetic deletion of CDK6 in vivo. Mechanistic and functional validation of resistance pathways was performed using CRISPR interference, immunoblotting, immunofluorescence, genetics, and pharmacology. Lipid quantification was carried out by ultra-high performance liquid chromatography-tandem mass spectrometry. RESULTS Our results reveal that decreased ribosomal protein expression underlies resistance to CDK6 inhibition in HH-associated medulloblastoma, leading to endoplasmic reticular (ER) stress and activation of the unfolded protein response (UPR). We show that ER stress and the UPR increase the activity of enzymes producing Smoothened-activating sterol lipids that sustain oncogenic HH signaling in medulloblastoma despite CDK6 inhibition. These discoveries suggest that combination molecular therapy against CDK6 and HSD11ß2, an enzyme producing Smoothened-activating lipids, may be an effective treatment for HH-associated medulloblastoma. In support of this hypothesis, we demonstrate that concurrent genetic deletion or pharmacological inhibition of CDK6 and HSD11ß2 additively blocks the growth of multiple models of HH-associated medulloblastoma in mice. CONCLUSIONS Smoothened-activating lipid biosynthesis underlies resistance to CDK6 inhibition in HH-associated medulloblastoma, revealing a novel combination therapy to treat the most common malignant brain tumor in children.
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Daggubati, Vikas, Jordan Hochstelter, Anirudh Bommireddy, Abrar Choudhury, Alexis Leigh Krup, Pervinder Choski, Pakteema Tong, et al. "EMBR-16. SMOOTHENED-ACTIVATING LIPIDS DRIVE RESISTANCE TO CDK4/6 INHIBITION IN HEDGEHOG-ASSOCIATED MEDULLOBLASTOMA." Neuro-Oncology 23, Supplement_1 (June 1, 2021): i9. http://dx.doi.org/10.1093/neuonc/noab090.034.
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Abstract Background Medulloblastoma is an aggressive pediatric brain tumor that is associated with misactivation of the Hedgehog (HH) pathway. Our lab has shown that CDK6, a critical activator of the cell cycle, is a direct transcriptional target of oncogenic HH signaling, and that inhibiting CDK6 blocks the growth of HH-associated medulloblastoma in mice. A clinical trial exploring the efficacy of CDK6 inhibition in medulloblastoma patients is underway, but prior attempts to target the HH pathway in medulloblastoma have been encumbered by resistance to molecular monotherapy. Thus, we sought to identify mechanisms of resistance to CDK6 inhibition in HH-associated medulloblastoma. Methods We performed orthogonal CRISPR and CRISPR interference screens in HH-associated medulloblastoma cells treated with pharmacologic inhibitors of CDK6 in vitro, and RNA-sequencing of HH-associated medulloblastomas with genetic deletion of CDK6 in vivo. Mechanistic and functional validation of resistance pathways was performed using CRISPR interference, immunoblotting, immunofluorescence, genetics, and pharmacology. Lipid quantification was carried out by ultra-high performance liquid chromatography-tandem mass spectrometry. Results Our results reveal that decreased ribosomal protein expression underlies resistance to CDK6 inhibition in HH-associated medulloblastoma, leading to endoplasmic reticular (ER) stress and activation of the unfolded protein response (UPR). We show that ER stress and the UPR increase the activity of enzymes producing Smoothened-activating sterol lipids that sustain oncogenic HH signaling in medulloblastoma despite CDK6 inhibition. These discoveries suggest that combination molecular therapy against CDK6 and HSD11ß2, an enzyme producing Smoothened-activating lipids, may be an effective treatment for HH-associated medulloblastoma. In support of this hypothesis, we demonstrate that concurrent genetic deletion or pharmacological inhibition of CDK6 and HSD11ß2 additively blocks the growth of multiple models of HH-associated medulloblastoma in mice. Conclusions Smoothened-activating lipid biosynthesis underlies resistance to CDK6 inhibition in HH-associated medulloblastoma, revealing a novel combination therapy to treat the most common malignant brain tumor in children.
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Daggubati, Vikas, Jordan Hochstelter, Ani Bommireddy, Abrar Choudhury, Alexis Krup, Pervinder Kaur, Pakteema Tong, et al. "DDRE-29. SMOOTHENED-ACTIVATING LIPIDS DRIVE RESISTANCE TO CDK4/6 INHIBITION IN HEDGEHOG-ASSOCIATED MEDULLOBLASTOMA." Neuro-Oncology 22, Supplement_2 (November 2020): ii67—ii68. http://dx.doi.org/10.1093/neuonc/noaa215.274.
Full textAbstract:
Abstract BACKGROUND Medulloblastoma is an aggressive pediatric brain tumor that is associated with misactivation of the Hedgehog (HH) pathway. Our lab has shown that CDK6, a critical activator of the cell cycle, is a direct transcriptional target of oncogenic HH signaling, and that inhibiting CDK6 blocks the growth of HH-associated medulloblastoma in mice. A clinical trial exploring the efficacy of CDK6 inhibition in medulloblastoma patients is underway, but prior attempts to target the HH pathway in medulloblastoma have been encumbered by resistance to molecular monotherapy. Thus, we sought to identify mechanisms of resistance to CDK6 inhibition in HH-associated medulloblastoma. METHODS We performed orthogonal CRISPR and CRISPR interference screens in HH-associated medulloblastoma cells treated with pharmacologic inhibitors of CDK6 in vitro, and RNA-sequencing of HH-associated medulloblastomas with genetic deletion of CDK6 in vivo. Mechanistic and functional validation of resistance pathways was performed using CRISPR interference, immunoblotting, immunofluorescence, genetics, and pharmacology. Lipid quantification was carried out by ultra-high performance liquid chromatography-tandem mass spectrometry. RESULTS Our results reveal that decreased ribosomal protein expression underlies resistance to CDK6 inhibition in HH-associated medulloblastoma, leading to endoplasmic reticular (ER) stress and activation of the unfolded protein response (UPR). We show that ER stress and the UPR increase the activity of enzymes producing Smoothened-activating sterol lipids that sustain oncogenic HH signaling in medulloblastoma despite CDK6 inhibition. These discoveries suggest that combination molecular therapy against CDK6 and HSD11ß2, an enzyme producing Smoothened-activating lipids, may be an effective treatment for HH-associated medulloblastoma. In support of this hypothesis, we demonstrate that concurrent genetic deletion or pharmacological inhibition of CDK6 and HSD11ß2 additively blocks the growth of multiple models of HH-associated medulloblastoma in mice. CONCLUSIONS Smoothened-activating lipid biosynthesis underlies resistance to CDK6 inhibition in HH-associated medulloblastoma, revealing a novel combination therapy to treat the most common malignant brain tumor in children.