Journal articles: 'LKB1/mTOR'

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Xiong, Yan, Ziye Xu, Yizhen Wang, Shihuan Kuang, and Tizhong Shan. "Adipocyte-specific DKO of Lkb1 and mTOR protects mice against HFD-induced obesity, but results in insulin resistance." Journal of Lipid Research 59, no. 6 (April 10, 2018): 974–81. http://dx.doi.org/10.1194/jlr.m081463.

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Liver kinase B1 (Lkb1) and mammalian target of rapamycin (mTOR) are key regulators of energy metabolism and cell growth. We have previously reported that adipocyte-specific KO of Lkb1 or mTOR in mice results in distinct developmental and metabolic phenotypes. Here, we aimed to assess how genetic KO of both Lkb1 and mTOR affects adipose tissue development and function in energy homeostasis. We used Adiponectin-Cre to drive adipocyte-specific double KO (DKO) of Lkb1 and mTOR in mice. We performed indirect calorimetry, glucose and insulin tolerance tests, and gene expression assays on the DKO and WT mice. We found that DKO of Lkb1 and mTOR results in reductions of brown adipose tissue and inguinal white adipose tissue mass, but in increases of liver mass. Notably, the DKO mice developed fatty liver and insulin resistance, but displayed improved glucose tolerance after high-fat diet (HFD)-feeding. Interestingly, the DKO mice were protected from HFD-induced obesity due to their higher energy expenditure and lower expression levels of adipogenic genes (CCAAT/enhancer binding protein α and PPARγ) compared with WT mice. These results together indicate that, compared with Lkb1 or mTOR single KOs, Lkb1/mTOR DKO in adipocytes results in overlapping and distinct metabolic phenotypes, and mTOR KO largely overrides the effect of Lkb1 KO.

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Jiang, Wenxiao, Yijun Zhang, Ye Huang, Yunfeng Cheng, and Zhigang Liu. "Effect of Hepatic Kinase B1 (LKB1) on Osteogenic Differentiation of Bone Marrow Mesenchymal Stem Cells During Senescence." Journal of Biomaterials and Tissue Engineering 10, no. 2 (February 1, 2020): 246–51. http://dx.doi.org/10.1166/jbt.2020.2247.

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Hepatic kinase B1 (LKB1) is a tumor suppressor and regulates cell proliferation and apoptosis. However, whether LKB1 affects bone marrow mesenchymal stem cells (BMSCs) osteogenic differentiation of during aging remains unclear. Two BMSCs derived from Zempster24−/− (aging) and Zempster24+/+ (normal) mice were cultured in vitro followed by measurement of LKB1 expression by real-time quantitative PCR and Western blot. LKB1 siRNA was transfected into Zempster24−/−BMSCs and LKB1 expression was measured. 14 days after osteogenic induction, mineralized nodule formation was evaluated by alizarin red staining, expression of Calcin, type I collagen, RUNX2 and OPN mRNA expression was measured, together with alkaline phosphatase (ALP) activity and the PI3K/mTOR pathway activity. Compared with normal BMSCs, LKB1 expression was significantly increased, calcified nodules were decreased, with reduced expression of osteocalcin, type I collagen, RUNX2 and OPN mRNA as well as decreased ALP activity and PI3K/mTOR signaling protein expression (P < 0.05). LKB1 siRNA transfection into senescent BMSCs down-regulated LKB1 expression, increased calcification nodule formation, expression of osteocalcin, type I collagen, RUNX2 and OPN mRNA, as well as increased ALP activity and PI3K/mTOR pathway protein expression (P < 0.05). Aging can promote the increase of LKB1 expression and inhibit the osteogenic differentiation of BMSCs. Down-regulation of LKB1 expression in BMSCs during senescence can promote osteogenic differentiation through regulating PI3K/mTOR pathway.

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Yilmaz, Emrullah, Lauren Averett Byers, Lixia Diao, Uma Giri, Jayanthi Gudikote, You Hong Fan, Jing Wang, et al. "Use of proteomic analysis of LKB1/AMPK/mTOR pathways to identify IGF-1R pathway upregulation with LKB1 loss or mTOR inhibition in NSCLC: Implications for targeted combinations." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 10612. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.10612.

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10612 Background: LKB1 is a serine/threonine kinase which is mutated in 20-30% of non-small cell lung cancers (NSCLC) and functions as a tumor suppressor by activating AMPK. Loss of LKB1 by point mutation or deletion suppresses AMPK, leading to increased mTOR signaling. We investigated the signaling pathways modulated by LKB1 mutations and by mTOR inhibition in NSCLC. Methods: Protein expression in cell lines was measured by reverse phase protein array. Differences in protein expression at baseline in LKB1 wild-type versus mutant cell lines and the effects of protein modulation by treatment were assessed by ANOVA. Results: LKB1 mutant cell lines had lower expression of phosphorylated AMPK and TSC (p<0.01 for both) consistent with prior observations. In addition, mutant cell lines expressed higher levels of proteins in the IGF1R pathway including IGFR1b (p<0.0001); AIB1, which is known to upregulate IGF1 (p<0.0001); and IGFBP2 (p=0.016). LKB1 mutant cell lines (n=11/25) were 1.5-fold more sensitive to the AMPK activator metformin, although this did not reach statistical significance (p=0.10). Expression levels of IGF1R pathway proteins increased significantly after 48h treatment with metformin, the mTOR inhibitor temsirolimus, and the dual PI3K/mTOR inhibitor PI103. For example, IGFBP2 and AIB1 were elevated after metformin treatment (p=0.02 and 0.005, respectively); IRS1 and IGFR1 were elevated after temsirolimus or PI103 (p<0.05 for both). Following treatment with metformin and temsirolimus, there was also increased pAkt, a downstream target of IGF1R and activator of mTOR (p<0.01 for both). Modulation of the IGF1R pathway by these drugs was independent of LKB1 mutation status. Conclusions: LKB1 mutant cell lines have increased IGFR activity with higher baseline IGFR1, IGFB2 and AIB1, suggesting that IGFR may be a potential therapeutic target in LKB1 mutant tumors. In addition, inhibition of the mTOR pathway upregulates the IGFR pathway possibly as a feedback mechanism. These results support the investigation of IGFR inhibitors in combination with drugs targeting the mTOR pathway, particularly for tumors bearing LKB1 mutations.

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Nishimura, Sadaaki, Masakazu Yashiro, Tomohiro Sera, Yurie Yamamoto, Yukako Kushitani, Atsushi Sugimoto, Shuhei Kushiyama, et al. "Serine threonine kinase 11/liver kinase B1 mutation in sporadic scirrhous-type gastric cancer cells." Carcinogenesis 41, no. 11 (March 31, 2020): 1616–23. http://dx.doi.org/10.1093/carcin/bgaa031.

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Abstract Scirrhous-type gastric carcinoma (SGC), which is characterized by the rapid proliferation of cancer cells accompanied by extensive fibrosis, shows extremely poor survival. A reason for the poor prognosis of SGC is that the driver gene responsible for SGC has not been identified. To identify the characteristic driver gene of SGC, we examined the genomic landscape of six human SGC cell lines of OCUM-1, OCUM-2M, OCUM-8, OCUM-9, OCUM-12 and OCUM-14, using multiplex gene panel testing by next-generation sequencing. In this study, the non-synonymous mutations of serine threonine kinase 11/liver kinase B1 (STK11/LKB1) gene were detected in OCUM-12, OCUM-2M and OCUM-14 among the six SGC cell lines. Capillary sequencing analysis confirmed the non-sense or missense mutation of STK11/LKB1 in the three cell lines. Western blot analysis showed that LKB1 expression was decreased in OCUM-12 cells and OCUM-14 cells harboring STK11/LKB1 mutation. The mammalian target of rapamycin (mTOR) inhibitor significantly inhibited the proliferation of OCUM-12 and OCUM-14 cells. The correlations between STK11/LKB1 expression and clinicopathologic features of gastric cancer were examined using 708 primary gastric carcinomas by immunochemical study. The low STK11/LKB1 expression group was significantly associated with SGC, high invasion depth and frequent nodal involvement, in compared with the high STK11/LKB1 expression group. Collectively, our study demonstrated that STK11/LKB1 mutation might be responsible for the progression of SGC, and suggested that mTOR signaling by STK11/LKB1 mutation might be one of therapeutic targets for patients with SGC.

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Paunovic, Verica, Stojan Peric, Irena Vukovic, Marina Stamenkovic, Emina Milosevic, Danijela Stevanovic, Milos Mandic, et al. "Downregulation of LKB1/AMPK Signaling in Blood Mononuclear Cells Is Associated with the Severity of Guillain–Barre Syndrome." Cells 11, no. 18 (September 16, 2022): 2897. http://dx.doi.org/10.3390/cells11182897.

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AMP-activated protein kinase (AMPK) is an intracellular energy sensor that regulates metabolic and immune functions mainly through the inhibition of the mechanistic target of rapamycin (mTOR)-dependent anabolic pathways and the activation of catabolic processes such as autophagy. The AMPK/mTOR signaling pathway and autophagy markers were analyzed by immunoblotting in blood mononuclear cells of 20 healthy control subjects and 23 patients with an acute demyelinating form of Guillain–Barré syndrome (GBS). The activation of the liver kinase B1 (LKB1)/AMPK/Raptor signaling axis was significantly reduced in GBS compared to control subjects. In contrast, the phosphorylated forms of mTOR activator AKT and mTOR substrate 4EBP1, as well as the levels of autophagy markers LC3-II, beclin-1, ATG5, p62/sequestosome 1, and NBR1 were similar between the two groups. The downregulation of LKB1/AMPK signaling, but not the activation status of the AKT/mTOR/4EBP1 pathway or the levels of autophagy markers, correlated with higher clinical activity and worse outcomes of GBS. A retrospective study in a diabetic cohort of GBS patients demonstrated that treatment with AMPK activator metformin was associated with milder GBS compared to insulin/sulphonylurea therapy. In conclusion, the impairment of the LKB1/AMPK pathway might contribute to the development/progression of GBS, thus representing a potential therapeutic target in this immune-mediated peripheral polyneuropathy.

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Yang, Jing, Chengxian Xu, Joseph Lechner, Haley Walls, and Kai Yang. "LKB1 regulates macrophage metabolism and functional polarization in immunomodulation." Journal of Immunology 210, no. 1_Supplement (May 1, 2023): 168.14. http://dx.doi.org/10.4049/jimmunol.210.supp.168.14.

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Abstract Macrophages play critical roles in maintaining tissue homeostasis and modulating immune responses. In response to microenvironmental cytokines, macrophages coordinate cellular signaling networks and diverse transcriptional programs to dictate their phenotypical and functional heterogeneity. For instance, LPS/IFNγ and IL-4 induce classically (M1) and alternatively (M2) activated macrophages, respectively. Remodeling cellular metabolism has been highlighted a key process underlying macrophage functional polarization. However, the precise mechanisms coordinating macrophage metabolism and polarization remain elusive. We report here that the kinase LKB1, a well-known negative regulator of mTOR signaling pathway, serves as a metabolic checkpoint that connects cellular metabolic reprogramming to functional polarization in macrophages. We found that genetic depletion of LKB1 in macrophages polarized their differentiation towards M2-like macrophages, characterized by enhanced expression of M2-associated markers, independently of mTOR and STAT6 signaling pathways. In contrast, loss of LKB1 had no substantial impact on M1-like macrophages. Moreover, LKB1-defienct macrophages orchestrated reprogramming of mitochondrial metabolism to facilitate M2 polarization and tumor immune evasion. Collectively, our studies establish a previously unappreciated role for LKB1 in connecting macrophage metabolism and functional polarization in modulating tumor immunity. This work was partially supported by the Herman B Wells Center and Riley Children’s Foundation.

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Zhou, Wei, Adam I. Marcus, and Paula M. Vertino. "Dysregulation of mTOR activity through LKB1 inactivation." Chinese Journal of Cancer 32, no. 8 (August 5, 2013): 427–33. http://dx.doi.org/10.5732/cjc.013.10086.

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Borkowsky, Sarah, Maximilian Gass, Azadeh Alavizargar, Johannes Hanewinkel, Ina Hallstein, Pavel Nedvetsky, Andreas Heuer, and Michael P. Krahn. "Phosphorylation of LKB1 by PDK1 Inhibits Cell Proliferation and Organ Growth by Decreased Activation of AMPK." Cells 12, no. 5 (March 6, 2023): 812. http://dx.doi.org/10.3390/cells12050812.

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The master kinase LKB1 is a key regulator of se veral cellular processes, including cell proliferation, cell polarity and cellular metabolism. It phosphorylates and activates several downstream kinases, including AMP-dependent kinase, AMPK. Activation of AMPK by low energy supply and phosphorylation of LKB1 results in an inhibition of mTOR, thus decreasing energy-consuming processes, in particular translation and, thus, cell growth. LKB1 itself is a constitutively active kinase, which is regulated by posttranslational modifications and direct binding to phospholipids of the plasma membrane. Here, we report that LKB1 binds to Phosphoinositide-dependent kinase (PDK1) by a conserved binding motif. Furthermore, a PDK1-consensus motif is located within the kinase domain of LKB1 and LKB1 gets phosphorylated by PDK1 in vitro. In Drosophila, knockin of phosphorylation-deficient LKB1 results in normal survival of the flies, but an increased activation of LKB1, whereas a phospho-mimetic LKB1 variant displays decreased AMPK activation. As a functional consequence, cell growth as well as organism size is decreased in phosphorylation-deficient LKB1. Molecular dynamics simulations of PDK1-mediated LKB1 phosphorylation revealed changes in the ATP binding pocket, suggesting a conformational change upon phosphorylation, which in turn can alter LKB1’s kinase activity. Thus, phosphorylation of LKB1 by PDK1 results in an inhibition of LKB1, decreased activation of AMPK and enhanced cell growth.

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Radu, Anca G., Sakina Torch, Florence Fauvelle, Karin Pernet-Gallay, Anthony Lucas, Renaud Blervaque, Véronique Delmas, et al. "LKB1 specifies neural crest cell fates through pyruvate-alanine cycling." Science Advances 5, no. 7 (July 2019): eaau5106. http://dx.doi.org/10.1126/sciadv.aau5106.

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Metabolic processes underlying the development of the neural crest, an embryonic population of multipotent migratory cells, are poorly understood. Here, we report that conditional ablation of the Lkb1 tumor suppressor kinase in mouse neural crest stem cells led to intestinal pseudo-obstruction and hind limb paralysis. This phenotype originated from a postnatal degeneration of the enteric nervous ganglia and from a defective differentiation of Schwann cells. Metabolomic profiling revealed that pyruvate-alanine conversion is enhanced in the absence of Lkb1. Mechanistically, inhibition of alanine transaminases restored glial differentiation in an mTOR-dependent manner, while increased alanine level directly inhibited the glial commitment of neural crest cells. Treatment with the metabolic modulator AICAR suppressed mTOR signaling and prevented Schwann cell and enteric defects of Lkb1 mutant mice. These data uncover a link between pyruvate-alanine cycling and the specification of glial cell fate with potential implications in the understanding of the molecular pathogenesis of neural crest diseases.

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Li, Yongqiang, Tao Sun, Shuxin Shen, Lixia Wang, and Jifeng Yan. "LncRNA DYNLRB2-2 inhibits THP-1 macrophage foam cell formation by enhancing autophagy." Biological Chemistry 400, no. 8 (July 26, 2019): 1047–57. http://dx.doi.org/10.1515/hsz-2018-0461.

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Abstract The aim of this study was to investigate whether long non-coding RNA (lncRNA) DYNLRB2-2 can inhibit foam cell formation by activating autophagy. The location of DYNLRB2-2 in THP-1-derived macrophages was analyzed by fluorescence in situ hybridization (FISH). Oxidized-low-density lipoprotein (ox-LDL) was used to induce the formation of foam cells, Oil Red O (ORO) staining and high-performance liquid chromatography (HPLC) were performed to detect accumulation of lipid droplets and the level of cholesterol concentration, respectively. The mRNA and protein level of ATP-binding cassette transporter A1 (ABCA1) were examined by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blotting. Relative protein levels of (p-) liver kinase B1 (LKB1), (p-) AMP-activated protein kinase (AMPK), (p-) the mammalian target of rapamycin (mTOR) and autophagy markers (LC3 II, Beclin-1 and p62) in THP-1 macrophage-derived foam cells were analyzed by Western blotting. The levels of inflammatory factors [tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1β] in THP-1 macrophage-derived foam cells were detected by enzyme-linked immunosorbent assay (ELISA). 3-MA and compound C were used to block autophagy. Our data show that DYNLRB2-2 inhibited the formation of THP-1 macrophage-derived foam cells and promotes cholesterol efflux (CE) by activating autophagy. DYNLRB2-2 caused autophagy by activating the signaling pathway of LKB1/AMPK/mTOR in foam cells. DYNLRB2-2 activated the LKB1/AMPK/mTOR signaling pathway via the miR-298/Sirtuin 3 (SIRT3) axis. Our data indicated that DYNLRB2-2 enhanced CE by regulating the LKB1/AMPK/mTOR autophagy signaling pathway through the miR-298/SIRT3 axis, thereby blocking the formation of foam cells from THP-1 macrophages.

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Wang, Yuan, Shan Zhu, Hongtao Liu, Wen Wei, Yi Tu, Chuang Chen, Junlong Song, et al. "Thyroxine Alleviates Energy Failure, Prevents Myocardial Cell Apoptosis, and Protects against Doxorubicin-Induced Cardiac Injury and Cardiac Dysfunction via the LKB1/AMPK/mTOR Axis in Mice." Disease Markers 2019 (December 18, 2019): 1–10. http://dx.doi.org/10.1155/2019/7420196.

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Background. Previous studies have demonstrated that energy failure is closely associated with cardiac injury. Doxorubicin (DOX) is a commonly used clinical chemotherapy drug that can mediate cardiac injury through a variety of mechanisms. Thyroxine is well known to play a critical role in energy generation; thus, this study is aimed at investigating whether thyroxine can attenuate DOX-induced cardiac injury by regulating energy generation. Methods. First, the effect of DOX on adenosine diphosphate (ADP) and adenosine triphosphate (ATP) ratios in mice was assessed. In addition, thyroxine was given to mice before they were treated with DOX to investigate the effects of thyroxine on DOX-induced cardiac injury. Furthermore, to determine whether the liver kinase b1 (LKB1)/adenosine 5′-monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) axis mediated the effect of thyroxine on DOX-induced cardiac injury, thyroxine was given to DOX-treated LKB1 knockout (KO) mice. Results. DOX treatment time- and dose-dependently increased the ADP/ATP ratio. Thyroxine treatment also reduced lactate dehydrogenase (LDH) and creatine kinase myocardial band (CK-MB) levels in both serum and heart tissue and alleviated cardiac dysfunction in DOX-treated mice. Furthermore, thyroxine reversed DOX-induced reductions in LKB1 and AMPK phosphorylation; mitochondrial complex I, III, and IV activity; and mitochondrial swelling and reversed DOX-induced increases in mTOR pathway phosphorylation and myocardial cell apoptosis. These effects of thyroxine on DOX-treated mice were significantly attenuated by LKB1 KO. Conclusions. Thyroxine alleviates energy failure, reduces myocardial cell apoptosis, and protects against DOX-induced cardiac injury via the LKB1/AMPK/mTOR axis in mice. Thyroxine may be a new agent for the clinical prevention of cardiac injury in tumor patients undergoing chemotherapy with DOX.

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Akasaka, Yasuyuki, Shun Hasei, Yukino Ohata, Machi Kanna, Yusuke Nakatsu, Hideyuki Sakoda, Midori Fujishiro, et al. "Auraptene Enhances AMP-Activated Protein Kinase Phosphorylation and Thereby Inhibits the Proliferation, Migration and Expression of Androgen Receptors and Prostate-Specific Antigens in Prostate Cancer Cells." International Journal of Molecular Sciences 24, no. 21 (November 6, 2023): 16011. http://dx.doi.org/10.3390/ijms242116011.

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Citrus hassaku extract reportedly activates AMPK. Because this extract contains an abundance of auraptene, we investigated whether pure auraptene activates AMPK and inhibits proliferation using prostate cancer cell lines. Indeed, auraptene inhibited the proliferation and migration of LNCaP cells and induced phosphorylation of AMPK or its downstream ACC in LNCaP, PC3, and HEK-293 cells, but not in DU145 cells not expressing LKB1. In addition, the mTOR-S6K pathway, located downstream from activated AMPK, was also markedly suppressed by auraptene treatment. Importantly, it was shown that auraptene reduced androgen receptor (AR) and prostate-specific antigen (PSA) expressions at both the protein and the mRNA level. This auraptene-induced downregulation of PSA was partially but significantly reversed by treatment with AMPK siRNA or the AMPK inhibitor compound C, suggesting AMPK activation to, at least partially, be causative. Finally, in DU145 cells lacking the LKB1 gene, exogenously induced LKB1 expression restored AMPK phosphorylation by auraptene, indicating the essential role of LKB1. In summary, auraptene is a potent AMPK activator that acts by elevating the AMP/ATP ratio, thereby potentially suppressing prostate cancer progression, via at least three molecular mechanisms, including suppression of the mTOR-S6K pathway, reduced lipid synthesis, and AR downregulation caused by AMPK activation.

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Shaw, Reuben J., Nabeel Bardeesy, Brendan D. Manning, Lyle Lopez, Monica Kosmatka, Ronald A. DePinho, and Lewis C. Cantley. "The LKB1 tumor suppressor negatively regulates mTOR signaling." Cancer Cell 6, no. 1 (July 2004): 91–99. http://dx.doi.org/10.1016/j.ccr.2004.06.007.

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Lee, H. R., J. Kim, S. J. Yoo, J. A. Park, and S. W. Kang. "POS0005 THE EFFECT OF LKB1 INHIBITION IN RA PATHOGENESIS." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 204.3–204. http://dx.doi.org/10.1136/annrheumdis-2021-eular.946.

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Background:Liver kinase B1 (LKB1) is known as a tumor suppressor gene and also inhibits reactive oxygen species (ROS) levels. Intracellular ROS are catalyzed by the enzyme complex nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX). We previously reported that NOX4 induced the migration and invasion of fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA). Although LKB1 is expected to alleviate synovial inflammation through ROS regulation, the role of LKB1 in RA has not been examined.Objectives:To explore whether LKB1 affects RA inflammation, we transfected LKB1 siRNA and analyzed related gene expressions in RA FLS.Methods:Synovial tissues were obtained from RA patients who were undergoing synovectomy or joint replacement. The isolated cells were cultured in Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 10% fetal bovine serum, 100 U/ml penicillin and 100 mg/ml streptomycin and maintained in a 5% CO2 incubator at 37 °C. FLS were used for experiments after four to six passages. Cells were transfected with lipofectamine transfection reagent and LKB1 siRNA duplex targeting constructs. After incubation for 24 h, downregulation of target expression was evaluated by real-time PCR and western blot analysis.Results:RA FLS was transfected with LKB1 siRNA and 90% of LKB1 mRNA expression was decreased. LKB1 knock-down also caused the decreased expression of mechanistic target of rapamycin (mTOR; 0.38 fold) and serine/threonine kinase (AKT) 2 (0.40 fold), which are downstream targets of LKB1. NOX4 was significantly increased (4.94 fold) by LKB1 inhibition. On the other side, the down regulated NOX4 induced significantly elevated LKB1 mRNA expression in RA FLS. When the expressions of proinflammatory cytokines were examined, IL-1β, IL-6, TNF-α were highly increased by LKB1 deficiency. FLS migration-related chemokines, IL-8 and MMP-3 were also enhanced compared to control.Conclusion:There was a negative correlation between NOX4 and LKB1 in RA FLS. As LKB1 deficiency induced the expression of proinflammatory cytokines and migration related chemokines, LKB1 could play a critical role in RA pathogenesis.References:[1]Bartok B, Firestein GS. Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis. Immunol Rev. 2010;233(1):233–55.[2]Mateen S, Moin S, Khan AQ, Zafar A, Fatima N. Increased reactive oxygen species formation and oxidative stress in rheumatoid arthritis. PLoS One. 2016;11(4):e0152925.Disclosure of Interests:None declared.

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Aznar, Nicolas, and Marc Billaud. "Primary Cilia Bend LKB1 and mTOR to Their Will." Developmental Cell 19, no. 6 (December 2010): 792–94. http://dx.doi.org/10.1016/j.devcel.2010.11.016.

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Zhao, Jimeng, Zhe Ma, Handan Zheng, Yan Huang, Luyi Wu, Huangan Wu, Yin Shi, Huirong Liu, and Yanan Liu. "Effects of Herb-Partitioned Moxibustion on Autophagy and Immune Activity in the Colon Tissue of Rats with Crohn’s Disease." Evidence-Based Complementary and Alternative Medicine 2022 (January 28, 2022): 1–12. http://dx.doi.org/10.1155/2022/3534874.

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Objective. To investigate the mechanism of action of herb-partitioned moxibustion on CD from the perspective of autophagy and immunity. Methods. The expression of microtubule-associated protein LC3II and SQSTM1/p62 in the colon tissues was detected by immunohistochemistry. Western blot was used to detect the expression of autophagic and immune-related proteins in the colon, such as LC3II, SQSTM1/p62, Beclin1, ATG16L1, NOD2, IRGM, IL-1β, IL-17, and TNF-β. mRNA levels of immune factors, such as IL-1β, IL-17, and TNF-β, and autophagy signaling molecules, such as PI3KC, AKT1, LKB1, and mTOR, were detected by RT-qPCR. Results. Herb-partitioned moxibustion reduced the protein levels of ATG16L1, NOD2, IRGM, LC3II, and Beclin1 ( P < 0.01 ) and both the protein and mRNA levels of IL-1β, IL-17, and TNF-β in CD rats ( P < 0.01 or P < 0.05 ), and it also increased the expression of SQSTM1/p62 protein ( P < 0.01 ). The modulatory effects of herb-partitioned moxibustion on ATG16L1, NOD2, IRGM, LC3II, TNF-β, and IL-17 protein and IL-1β protein and mRNA were better than those of mesalazine ( P < 0.01 or P < 0.05 ). Herb-partitioned moxibustion also reduced colon PI3KC, AKT1, and LKB1 mRNA expressions in CD rats ( P < 0.01 or P < 0.05 ) and increased mTOR protein expression ( P < 0.05 ). And the modulatory effect of herb-partitioned moxibustion on AKT1 mRNA was better than that of mesalazine ( P < 0.05 ). Conclusion. Herb-partitioned moxibustion may inhibit excessively activated autophagy and modulate the expression of immune-related factors by regulating the LKB1-mTOR-PI3KC signal transduction networks, thereby alleviating intestinal inflammation in CD rats.

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Xu, Ziye, Wenjing You, Fengqin Wang, Yizhen Wang, and Tizhong Shan. "Elucidating the role of Lkb1 and mTOR in adipose tissue." Adipocyte 8, no. 1 (October 20, 2018): 26–30. http://dx.doi.org/10.1080/21623945.2018.1535743.

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Treilleux, Isabelle, Monica Arnedos, Claire Cropet, Jean-Marc Ferrero, Sophie Abadie Lacourtoisie, Dominique Spaeth, Christelle Levy, et al. "Predictive markers of everolimus efficacy in hormone receptor positive (HR+) metastatic breast cancer (MBC): Final results of the TAMRAD trial translational study." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 510. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.510.

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510 Background: Hormone resistance is linked in part to cross-talk between ER signalling and PI3K/Akt/mTOR pathway. Following results of the BOLERO-2 trial, everolimus (E), a potent mTOR inhibitor, has recently been approved in combination with exemestane in women with HR+ MBC refractory to aromatase inhibitor (AI). However, E is frequently associated with specific toxicities, and predictive markers of efficacy are needed. We report here the final results of translational studies within the TAMRAD randomized Phase II trial, comparing tamoxifen (TAM) to TAM+E in AI pre-treated MBC. Methods: Tumor samples from 51 patients among the 111 treated in the TAMRAD trial were retrieved. Hot spot mutations of PI3K (exon 9-20), and KRAS (exon 2) were described. TMA analysis evaluated IHC expression of PTEN, pAkt, PI3K, LKB1, S6K, pS6K, 4EBP1, p4EBP1, and eIF4E. Exploratory analysis of E efficacy in each biomarker subgroup (high vs low expression defined by median percentage of marked cells) was done. Results: Patients characteristics and treatment efficacy among this sub-population were similar to the results from the whole population: Time to progression was 10 months for the TAM+E treated patients vs. 5.5 months for the TAM treated patients, HR: 0.59 (95% CI 0.33-1.07). PI3K-Akt pathway: All patients derived benefit from E regardless of PI3K mutational status, PTEN or pAkt expression. Surprisingly, E efficacy was greater in patients with low PI3K expression (n=12, HR=0.11, 95%CI 0.01-0.96) than in patients with high PI3K expression (n= 28, HR=0.9; 95%CI 0.49-2.41) PI3K independent pathway: Patients with low expression of the anti-oncogene LKB1 derived greater benefit from E (n=22, HR=0.33; 95%CI 0.13-0.89) than patients with high LKB1 expression (n=25, HR=0.75; 95%CI 0.32-1.74) mTOR downstream effectors: Patients with high p4EBP1 (n=27, HR=0.37; 95%CI 0.15-0.90) or low 4EBP1 (n=21, HR=0.39; 95%CI 0.14-1.08) were the subgroups most likely to benefit from E. Conclusions: Those results are in favor of a better efficacy of E for patients with PI3K independent activation of mTOR. If confirmed, they could have important implications for future patient selection. Clinical trial information: NCT01298713.

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Huang, Xu, Stephan Wullschleger, Natalia Shpiro, Victoria A. McGuire, Kei Sakamoto, Yvonne L. Woods, Wendy Mcburnie, Stewart Fleming, and Dario R. Alessi. "Important role of the LKB1–AMPK pathway in suppressing tumorigenesis in PTEN-deficient mice." Biochemical Journal 412, no. 2 (May 14, 2008): 211–21. http://dx.doi.org/10.1042/bj20080557.

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The LKB1 tumour suppressor phosphorylates and activates AMPK (AMP-activated protein kinase) when cellular energy levels are low, thereby suppressing growth through multiple pathways, including inhibiting the mTORC1 (mammalian target of rapamycin complex 1) kinase that is activated in the majority of human cancers. Blood glucose-lowering Type 2 diabetes drugs also induce LKB1 to activate AMPK, indicating that these compounds could be used to suppress growth of tumour cells. In the present study, we investigated the importance of the LKB1–AMPK pathway in regulating tumorigenesis in mice resulting from deficiency of the PTEN (phosphatase and tensin homologue deleted on chromosome 10) tumour suppressor, which drives cell growth through overactivation of the Akt and mTOR (mammalian target of rapamycin) kinases. We demonstrate that inhibition of AMPK resulting from a hypomorphic mutation that decreases LKB1 expression does not lead to tumorigenesis on its own, but markedly accelerates tumour development in PTEN+/− mice. In contrast, activating the AMPK pathway by administration of metformin, phenformin or A-769662 to PTEN+/− mice significantly delayed tumour onset. We demonstrate that LKB1 is required for activators of AMPK to inhibit mTORC1 signalling as well as cell growth in PTEN-deficient cells. Our findings highlight, using an animal model relevant to understanding human cancer, the vital role that the LKB1–AMPK pathway plays in suppressing tumorigenesis resulting from loss of the PTEN tumour suppressor. They also suggest that pharmacological inhibition of LKB1 and/or AMPK would be undesirable, at least for the treatment of cancers in which the mTORC1 pathway is activated. Most importantly, our results demonstrate the potential of AMPK activators, such as clinically approved metformin, as anticancer agents, which will suppress tumour development by triggering a physiological signalling pathway that potently inhibits cell growth.

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Sun, Gao, Andrei I. Tarasov, James A. McGinty, Paul M. French, Angela McDonald, Isabelle Leclerc, and Guy A. Rutter. "LKB1 deletion with the RIP2.Cre transgene modifies pancreatic β-cell morphology and enhances insulin secretion in vivo." American Journal of Physiology-Endocrinology and Metabolism 298, no. 6 (June 2010): E1261—E1273. http://dx.doi.org/10.1152/ajpendo.00100.2010.

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The tumor suppressor liver kinase B1 (LKB1), also called STK11, is a protein kinase mutated in Peutz-Jeghers syndrome. LKB1 phosphorylates AMP-activated protein kinase (AMPK) and several related protein kinases. Whereas deletion of both catalytic isoforms of AMPK from the pancreatic β-cell and hypothalamic neurons using the rat insulin promoter (RIP2). Cre transgene (βAMPKdKO) diminishes insulin secretion in vivo, deletion of LKB1 in the β-cell with an inducible Pdx-1.CreER transgene enhances insulin secretion in mice. To determine whether the differences between these models reflect genuinely distinct roles for the two kinases in the β-cell or simply differences in the timing and site(s) of deletion, we have therefore created mice deleted for LKB1 with the RIP2.Cre transgene. In marked contrast to βAMPKdKO mice, βLKB1KO mice showed diminished food intake and weight gain, enhanced insulin secretion, unchanged insulin sensitivity, and improved glucose tolerance. In line with the phenotype of Pdx1- CreER mice, total β-cell mass and the size of individual islets and β-cells were increased and islet architecture was markedly altered in βLKB1KO islets. Signaling by mammalian target of rapamycin (mTOR) to eIF4-binding protein-1 and ribosomal S6 kinase was also enhanced. In contrast to Pdx1- CreER-mediated deletion, the expression of Glut2, glucose-induced changes in membrane potential and intracellular Ca2+ were sharply reduced in βLKB1KO mouse islets and the stimulation of insulin secretion was modestly inhibited. We conclude that LKB1 and AMPK play distinct roles in the control of insulin secretion and that the timing of LKB1 deletion, and/or its loss from extrapancreatic sites, influences the final impact on β-cell function.

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Bi, Chengfeng, Chunsun Jiang, Xiaoxing Jiang, Xin Huang, Mario R. Fernandez, Javeed Iqbal, Robert E. Lewis, Wing Chung Chan, Timothy McKeithan, and Kai Fu. "The Mir-17∼92 Cluster Activates mTORC1 Signaling in MCL by Targeting Multiple Regulators of the LKB1/AMPK/mTOR Pathway." Blood 120, no. 21 (November 16, 2012): 5118. http://dx.doi.org/10.1182/blood.v120.21.5118.5118.

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Abstract Abstract 5118 Mantle cell lymphoma (MCL) is an aggressive hematological malignancy with a median survival ranging between 3 and 5 years. Novel therapeutic strategies are urgently needed to improve the outcome. Mammalian target of rapamycin (mTOR) pathway which plays a central role in controlling cell growth, proliferation and metabolism has been shown to be deregulated in MCL. mTOR inhibitors, such as rapamycin and its analogues, have been approved for treatment of relapsed/refractory MCL. However, the molecular mechanism of mTOR activation in MCL has yet to be defined. MiRNA (miR)-17∼92 is a cluster of six miRNAs which are frequently overexpressed in MCL cases and overexpression of the miR-17∼92 cluster in MCL predicts poor prognosis. Our previous study demonstrated that miR-17∼92 activated the PI3K/AKT pathway by directly targeting PTEN and PHLPP2; and knock-down of miR-17∼92 expression inhibited MCL tumor growth in a xenograft/SCID MCL mouse model. In the present study, we further demonstrated that knock-down miR-17∼92 decreased the cell size, similar effect as seen in cells treated with mTORC1 inhibitors. Knockdown of miR-17∼92 expression also decreased the glycolysis, protein synthesis and glucose uptake in MCL cells. We found that knockdown miR-17∼92 activated AMPK signaling as demonstrated by increased phosphorylation of AMPK at Thr172, especially under low glucose condition. Activated AMPK further phosphorylated TSC2 and Raptor at S1387 and S792, respectively, thereby inhibiting mTORC1 signaling as evidenced by decreased phosphorylation of RPS6 and 4E-BP1. Using TargetScan and other prediction algorithms, we found that several factors in the LKB1/AMPK/mTOR pathway, such as LKB1, CAB39, PRKAA1 and TSC1, are predicted the targets of miR-17∼92. In this study, we validated these factors as direct targets of the miR-17∼92 by 3'UTR luciferase assays using reporter plasmids containing the 3'UTR of the targets or the 3'UTR with mutations in the predicted miRNA binding sites. The protein levels of these targets decreased in MCL cells with the miR-17∼92 overexpression. Conversely, the levels of these factors were increased upon knockdown of miR-17∼92 cluster. Our results indicate that overexpression of miR-17∼92 in MCL plays important role in mTORC1 activation by inactivating the LKB1/AMPK signaling, in addition to its effect on the PI3K/AKT pathway activation. Disclosures: No relevant conflicts of interest to declare.

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Han, Dong, Shao-Jun Li, Yan-Ting Zhu, Lu Liu, and Man-Xiang Li. "LKB1/AMPK/mTOR Signaling Pathway in Non-small-cell Lung Cancer." Asian Pacific Journal of Cancer Prevention 14, no. 7 (July 30, 2013): 4033–39. http://dx.doi.org/10.7314/apjcp.2013.14.7.4033.

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Jiménez-Mora, Eva, Beatriz Gallego, Sergio Díaz-Gago, Marina Lasa, Pablo Baquero, and Antonio Chiloeches. "V600EBRAF Inhibition Induces Cytoprotective Autophagy through AMPK in Thyroid Cancer Cells." International Journal of Molecular Sciences 22, no. 11 (June 3, 2021): 6033. http://dx.doi.org/10.3390/ijms22116033.

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The dysregulation of autophagy is important in the development of many cancers, including thyroid cancer, where V600EBRAF is a main oncogene. Here, we analyse the effect of V600EBRAF inhibition on autophagy, the mechanisms involved in this regulation and the role of autophagy in cell survival of thyroid cancer cells. We reveal that the inhibition of V600EBRAF activity with its specific inhibitor PLX4720 or the depletion of its expression by siRNA induces autophagy in thyroid tumour cells. We show that V600EBRAF downregulation increases LKB1-AMPK signalling and decreases mTOR activity through a MEK/ERK-dependent mechanism. Moreover, we demonstrate that PLX4720 activates ULK1 and increases autophagy through the activation of the AMPK-ULK1 pathway, but not by the inhibition of mTOR. In addition, we find that autophagy blockade decreases cell viability and sensitize thyroid cancer cells to V600EBRAF inhibition by PLX4720 treatment. Finally, we generate a thyroid xenograft model to demonstrate that autophagy inhibition synergistically enhances the anti-proliferative and pro-apoptotic effects of V600EBRAF inhibition in vivo. Collectively, we uncover a new role of AMPK in mediating the induction of cytoprotective autophagy by V600EBRAF inhibition. In addition, these data establish a rationale for designing an integrated therapy targeting V600EBRAF and the LKB1-AMPK-ULK1-autophagy axis for the treatment of V600EBRAF-positive thyroid tumours.

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Xiao, Jia, Rui Guo, Man-Lung Fung, Emily C. Liong, Raymond Chuen Chung Chang, Yick-Pang Ching, and George L. Tipoe. "Garlic-Derived S-Allylmercaptocysteine Ameliorates Nonalcoholic Fatty Liver Disease in a Rat Model through Inhibition of Apoptosis and Enhancing Autophagy." Evidence-Based Complementary and Alternative Medicine 2013 (2013): 1–11. http://dx.doi.org/10.1155/2013/642920.

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Our previous study demonstrated that administration of garlic-derived antioxidant S-allylmercaptocysteine (SAMC) ameliorated hepatic injury in a nonalcoholic fatty liver disease (NAFLD) rat model. Our present study aimed to investigate the mechanism of SAMC on NAFLD-induced hepatic apoptosis and autophagy. Adult female rats were fed with a high-fat diet for 8 weeks to develop NAFLD with or without intraperitoneal injection of 200 mg/kg SAMC for three times per week. During NAFLD development, increased apoptotic cells and caspase-3 activation were observed in the liver. Increased apoptosis was modulated through both intrinsic and extrinsic apoptotic pathways. NAFLD treatment also enhanced the expression of key autophagic markers in the liver with reduced activity of LKB1/AMPK and PI3K/Akt pathways. Increased expression of proapoptotic regulator p53 and decreased activity of antiautophagic regulator mTOR were also observed. Administration of SAMC reduced the number of apoptotic cells through downregulation of both intrinsic and extrinsic apoptotic mechanisms. SAMC also counteracted the effects of NAFLD on LKB1/AMPK and PI3K/Akt pathways. Treatment with SAMC further enhanced hepatic autophagy by regulating autophagic markers and mTOR activity. In conclusion, administration of SAMC during NAFLD development in rats protects the liver from chronic injury by reducing apoptosis and enhancing autophagy.

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Tzatsos, Alexandros, and Konstantin V. Kandror. "Nutrients Suppress Phosphatidylinositol 3-Kinase/Akt Signaling via Raptor-Dependent mTOR-Mediated Insulin Receptor Substrate 1 Phosphorylation." Molecular and Cellular Biology 26, no. 1 (January 1, 2006): 63–76. http://dx.doi.org/10.1128/mcb.26.1.63-76.2006.

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ABSTRACT Nutritional excess and/or obesity represent well-known predisposition factors for the development of non-insulin-dependent diabetes mellitus (NIDDM). However, molecular links between obesity and NIDDM are only beginning to emerge. Here, we demonstrate that nutrients suppress phosphatidylinositol 3 (PI3)-kinase/Akt signaling via Raptor-dependent mTOR (mammalian target of rapamycin)-mediated phosphorylation of insulin receptor substrate 1 (IRS-1). Raptor directly binds to and serves as a scaffold for mTOR-mediated phosphorylation of IRS-1 on Ser636/639. These serines lie close to the Y632MPM motif that is implicated in the binding of p85α/p110α PI3-kinase to IRS-1 upon insulin stimulation. Phosphomimicking mutations of these serines block insulin-stimulated activation of IRS-1-associated PI3-kinase. Knockdown of Raptor as well as activators of the LKB1/AMPK pathway, such as the widely used antidiabetic compound metformin, suppress IRS-1 Ser636/639 phosphorylation and reverse mTOR-mediated inhibition on PI3-kinase/Akt signaling. Thus, diabetes-related hyperglycemia hyperactivates the mTOR pathway and may lead to insulin resistance due to suppression of IRS-1-dependent PI3-kinase/Akt signaling.

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Shaw, R. J. "LKB1 and AMP-activated protein kinase control of mTOR signalling and growth." Acta Physiologica 196, no. 1 (May 2009): 65–80. http://dx.doi.org/10.1111/j.1748-1716.2009.01972.x.

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Green, Alexa S., Nicolas Chapuis, Thiago Trovati Maciel, Lise Willems, Mireille Lambert, Christophe Arnoult, Olivier Boyer, et al. "The LKB1/AMPK signaling pathway has tumor suppressor activity in acute myeloid leukemia through the repression of mTOR-dependent oncogenic mRNA translation." Blood 116, no. 20 (November 18, 2010): 4262–73. http://dx.doi.org/10.1182/blood-2010-02-269837.

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Abstract Finding an effective treatment for acute myeloid leukemia (AML) remains a challenge, and all cellular processes that are deregulated in AML cells should be considered in the design of targeted therapies. We show in our current study that the LKB1/AMPK/TSC tumor suppressor axis is functional in AML and can be activated by the biguanide molecule metformin, resulting in a specific inhibition of mammalian target of rapamycin (mTOR) catalytic activity. This induces a multisite dephosphorylation of the key translation regulator, 4E-BP1, which markedly inhibits the initiation step of mRNA translation. Consequently, metformin reduces the recruitment of mRNA molecules encoding oncogenic proteins to the polysomes, resulting in a strong antileukemic activity against primary AML cells while sparing normal hematopoiesis ex vivo and significantly reducing the growth of AML cells in nude mice. The induction of the LKB1/AMPK tumor-suppressor pathway thus represents a promising new strategy for AML therapy.

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Moore, Timothy M., Xavier M. Mortensen, Conrad K. Ashby, Alexander M. Harris, Karson J. Kump, David W. Laird, Aaron J. Adams, Jeremy K. Bray, Ting Chen, and David M. Thomson. "The effect of caffeine on skeletal muscle anabolic signaling and hypertrophy." Applied Physiology, Nutrition, and Metabolism 42, no. 6 (June 2017): 621–29. http://dx.doi.org/10.1139/apnm-2016-0547.

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Caffeine is a widely consumed stimulant with the potential to enhance physical performance through multiple mechanisms. However, recent in vitro findings have suggested that caffeine may block skeletal muscle anabolic signaling through AMP-activated protein kinase (AMPK)-mediated inhibition of mechanistic target of rapamycin (mTOR) signaling pathway. This could negatively affect protein synthesis and the capacity for muscle growth. The primary purpose of this study was to assess the effect of caffeine on in vivo AMPK and mTOR pathway signaling, protein synthesis, and muscle growth. In cultured C2C12 muscle cells, physiological levels of caffeine failed to impact mTOR activation or myoblast proliferation or differentiation. We found that caffeine administration to mice did not significantly enhance the phosphorylation of AMPK or inhibit signaling proteins downstream of mTOR (p70S6k, S6, or 4EBP1) or protein synthesis after a bout of electrically stimulated contractions. Skeletal muscle-specific knockout of LKB1, the primary AMPK activator in skeletal muscle, on the other hand, eliminated AMPK activation by contractions and enhanced S6k, S6, and 4EBP1 activation before and after contractions. In rats, the addition of caffeine did not affect plantaris hypertrophy induced by the tenotomy of the gastrocnemius and soleus muscles. In conclusion, caffeine administration does not impair skeletal muscle load-induced mTOR signaling, protein synthesis, or muscle hypertrophy.

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Lemoine, Manuela, Enrico Derenzini, Daniela Buglio, L. Jeffrey Medeiros, R. Eric Davis, Jiexin Zhang, Yuan Ji, and Anas Younes. "The pan-deacetylase inhibitor panobinostat induces cell death and synergizes with everolimus in Hodgkin lymphoma cell lines." Blood 119, no. 17 (April 26, 2012): 4017–25. http://dx.doi.org/10.1182/blood-2011-01-331421.

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AbstractThe pan-deacetylase inhibitor panobinostat (LBH589) recently has been shown to have significant clinical activity in patients with relapsed Hodgkin lymphoma, but its mechanism of action in Hodgkin lymphoma remains unknown. In this study, we demonstrate that panobinostat has potent antiproliferative activity against Hodgkin lymphoma–derived cell lines. At the molecular level, panobinostat activated the caspase pathway, inhibited STAT5 and STAT6 phosphorylation, and down-regulated hypoxia-inducible factor 1 α and its downstream targets, glucose transporter 1 (GLUT1) and vascular endothelial growth factor. Paradoxically, panobinostat inhibited LKB1 and AMP-activated protein kinase, leading to activation of mammalian target of rapamycin (mTOR) that promotes survival. Combining panobinostat with the mTOR inhibitor everolimus (RAD001) inhibited panobinostat-induced mTOR activation and enhanced panobinostat antiproliferative effects. Collectively, our data demonstrate that panobinostat is a potent deacetylase inhibitor against Hodgkin lymphoma–derived cell lines, and provide a mechanistic rationale for combining panobinostat with mTOR inhibitors for treating Hodgkin lymphoma patients. Furthermore, the effect of panobinostat on GLUT1 expression suggests that panobinostat may modulate the results of clinical diagnostic imaging tests that depend of functional GLUT1, such as fluorodeoxyglucose positron emission tomography.

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Jung, Taek-Yeol, Jae-Eun Ryu, Mi-Mi Jang, Soh-Yeon Lee, Gyu-Rin Jin, Chan-Woo Kim, Chae-Young Lee, et al. "Naa20, the catalytic subunit of NatB complex, contributes to hepatocellular carcinoma by regulating the LKB1–AMPK–mTOR axis." Experimental & Molecular Medicine 52, no. 11 (November 2020): 1831–44. http://dx.doi.org/10.1038/s12276-020-00525-3.

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AbstractN-α-acetyltransferase 20 (Naa20), which is a catalytic subunit of the N-terminal acetyltransferase B (NatB) complex, has recently been reported to be implicated in hepatocellular carcinoma (HCC) progression and autophagy, but the underlying mechanism remains unclear. Here, we report that based on bioinformatic analysis of Gene Expression Omnibus and The Cancer Genome Atlas data sets, Naa20 expression is much higher in HCC tumors than in normal tissues, promoting oncogenic properties in HCC cells. Mechanistically, Naa20 inhibits the activity of AMP-activated protein kinase (AMPK) to promote the mammalian target of rapamycin signaling pathway, which contributes to cell proliferation, as well as autophagy, through its N-terminal acetyltransferase (NAT) activity. We further show that liver kinase B1 (LKB1), a major regulator of AMPK activity, can be N-terminally acetylated by NatB in vitro, but also probably by NatB and/or other members of the NAT family in vivo, which may have a negative effect on AMPK activity through downregulation of LKB1 phosphorylation at S428. Indeed, p-LKB1 (S428) and p-AMPK levels are enhanced in Naa20-deficient cells, as well as in cells expressing the nonacetylated LKB1-MPE mutant; moreover, importantly, LKB1 deficiency reverses the molecular and cellular events driven by Naa20 knockdown. Taken together, our findings suggest that N-terminal acetylation of LKB1 by Naa20 may inhibit the LKB1–AMPK signaling pathway, which contributes to tumorigenesis and autophagy in HCC.

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Colombo, Marika, Matteo Demetrio Tripodi, Gabriel Caso, Elisa Perin, Mirko Marabese, Massimo Broggini, and Elisa Caiola. "Abstract 6346: Identification of ERK inhibitor-based combinations targeting LKB1-mutated NSCLC." Cancer Research 82, no. 12_Supplement (June 15, 2022): 6346. http://dx.doi.org/10.1158/1538-7445.am2022-6346.

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Abstract Background: Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide. It is a very heterogeneous disease where some frequent mutations remain untargetable. Among them there are those affecting STK11/LKB1, the third most commonly mutated gene in NSCLC adenocarcinomas. Patients harboring LKB1-mutated tumors often have a poor prognosis due to the aggressiveness of this type of cancer and the lack of specific and efficacious therapies. Previous studies in our laboratory demonstrated a peculiar in vitro and in vivo activity of ERK inhibitors (ERKi) on LKB1-mutated NSCLC preclinical models. However, due to the huge heterogeneity of this type of tumor, it is likely that ERKi alone will have limited clinical application. In this scenario, the aim of this project is to find ERKi synthetic lethal partners in order to enlarge NSCLC patient population amenable to this therapy. Methods: We performed high-throughput screenings of a FDA-approved drug library on two different cell line systems (LU99 and H358) each composed by the LKB1 wild-type (wt) parental cell line and the CRISPR-CAS9-derived LKB1 deleted clone. In both the screenings, we treated the cell lines with the FDA-approved library alone or in combination with a subtoxic concentration of the ERKi. Results: According to our aim, for each screening, we analyzed the results selecting as hits those combinations preferentially active on the LKB1-deleted clones compared to their LKB1-wt cell lines. We verified that the FDA-approved compounds were subtoxic when used as single treatment in both the parental cell lines and their clones. We highlighted 28 and 42 hit combinations for LU99 and H358 isogenic systems, respectively. Some hits were common between the two screenings and the most represented FDA-approved drug’s classes of the hit combinations were PI3K/Akt/mTOR inhibitors, tyrosine kinase receptor inhibitors, MAPK inhibitors and compounds involved in anti-inflammatory pathways neuronal signaling, metabolism and DNA damage. Among the hits, we have cross-validated 4 ERKi-based combinations (a tyrosin kinase inhibitor, a MAPK inhibitor, a serine-threonine selective protein inhibitor and a farnesyl transferase inhibitor) in four different isogenic systems and we are now performing further validation on a panel of NSCLC cell lines with different LKB1-status as well as on NSCLC organoids. Conclusions: From the FDA-approved drug library screenings, different ERKi-based combinations showed promising results worthy to be deeply studied. Further analyses are ongoing to verify their efficacy on more complex models as NSCLC 3D organoids and to clarify the mechanism of action at the basis of the hit combinations. Positive results could give the chance to develop effective and specific therapies for patient with LKB1-mutated NSCLCs. Citation Format: Marika Colombo, Matteo Demetrio Tripodi, Gabriel Caso, Elisa Perin, Mirko Marabese, Massimo Broggini, Elisa Caiola. Identification of ERK inhibitor-based combinations targeting LKB1-mutated NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6346.

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Yang, Cong, Hongyu Ding, Yang Yang, Long Yang, Yun Yang, Meimiao Fang, Jin Ren, Ronggui Hu, Chengcheng Wang, and Wujun Geng. "BAP1 regulates AMPK-mTOR signalling pathway through deubiquitinating and stabilizing tumour-suppressor LKB1." Biochemical and Biophysical Research Communications 529, no. 4 (September 2020): 1025–32. http://dx.doi.org/10.1016/j.bbrc.2020.05.223.

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Regina, Sandra, Jean-Baptiste Valentin, Sébastien Lachot, Bruno Giraudeau, Jerome Rollin, and Yves Gruel. "Alterations of P53 and PTEN Genes Are Associated with Increased TF Expression and Reduced Survival in Non Small Cell Lung Cancer." Blood 112, no. 11 (November 16, 2008): 1032. http://dx.doi.org/10.1182/blood.v112.11.1032.1032.

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Abstract Introduction: Tissue Factor (TF) is the main initiator of blood coagulation and also a signalling protein that regulates cancerous cell migration, angiogenesis and metastasis. TF is frequently synthesized by many tumor cells and TF gene expression can be modulated by tumor suppressor genes (TSG) such as P53 and PTEN. Moreover, heparanase is an endo-b-D-glucuronidase also implicated in tumor development and was recently described to enhance TF expression and activity. Finally, another TSG, LKB1 that regulates the mTOR pathway with P53 and PTEN, has also been recently shown to modulate cancer differentiation and metastasis. Aim of the study: To look for a relationship between TF and heparanase genes expression in NSCLC and to investigate whether these genes can be regulated by P53, PTEN and LKB1. Material and Methods: TF and heparanase mRNA levels were measured by real-time PCR in lung tumors surgically removed in 53 Caucasian patients with NSCLC. Direct sequencing of exons 5–8 of P53 was performed on genomic DNA. Mutations of PTEN and LKB1 were screened by multiplex ligation dependant probe amplification using specific SALSA-MLPA kits (MRC-Holland, Amsterdam, Holland). Results were analyzed and compared to clinicopathological features using the Mann Whitney U-test and Fisher’s exact test. Moreover, survival analysis was evaluated using the Kaplan Meier method and differences assessed by the Log-rank test. Results: TF mRNA levels were variable from one sample to another (median: 11540 copies/108 copies of 18S RNA; range: 10–310 000) but significantly higher in T3–T4 tumors (19150 vs 8530 copies in T1–T2 tumors; p=0.04) and in stages III–IV of NSCLC (17710 vs 9780 copies in stages 1–2; p=0.03) as previously reported (Regina et al, J Thorac Oncol, 2008). Mutations of P53, LKB1 and PTEN were identified in 37.7 % (20/53), 49 % (26/53) and in 37.7 % (20/53) of tumors, respectively. TF mRNA levels were higher in samples mutated for P53 (median in P53Mut: 15655 vs 6225 copies/108 copies of 18S RNA in P53WT tissues; p=0.02), and also in cancerous tissues in whom PTEN mutations had been evidenced (median in PTENMut: 17370 vs 8530 copies in PTENWT; p=0.03). On the other hand, TF gene expression was unaffected in tumors when LKB1 mutations were detected alone but it dramatically increased if combined genetic alterations were present, with a number of mRNA copies varying from 3500 when no mutation was detected to 11600, 15800, and 78 000 copies when 1, 2 and 3 TSG were mutated (Spearman correlation p=0.01). Heparanase mRNA levels measured in lung tumors were also variable (median: 2922 copie/108 copies of 18S RNA; range: 80–39750), without any correlation with TF gene expression, TSG mutations and clinicopathological features. In contrast, the median survival time was shorter in patients with tumor TF mRNA levels above median value (26 vs 66 months; Hazard ratio: 1.96; CI95%:1.01–3.8; p=0.04) and when P53 was mutated (33 vs 43 months; Hazard ratio: 1.5; CI95%:1.02–2.5; p=0.05). Conclusion: This study provides evidence that combined oncogene events affecting TSG, such as P53, PTEN and LKB1, dramatically affect TF gene expression in NSCLC, this process contributing to cancer progression. TSG directly stimulate the mTOR pathway that could also be activated by TF/VIIa/XA complexes, favoring tumor cell migration.

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Tsai, Hui-Jen, Tsung-Ming Chang, Yan-Shen Shan, Pei-Yi Chu, Shih Sheng Jiang, Wen-Chun Hung, Yu-Lin Chen, Hsu-Chi Tu, and Li-Tzong Chen. "The regulatory role of PTEN and LKB1 on mTOR pathway in pancreatic neuroendocrien tumors." Pancreatology 17, no. 3 (July 2017): S11. http://dx.doi.org/10.1016/j.pan.2017.05.035.

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Green, Alexa S., Nicolas Chapuis, Catherine Lacombe, Patrick Mayeux, Didier Bouscary, and Jerome Tamburini. "LKB1/AMPK/mTOR signaling pathway in hematological malignancies: From metabolism to cancer cell biology." Cell Cycle 10, no. 13 (July 2011): 2115–20. http://dx.doi.org/10.4161/cc.10.13.16244.

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Lazo-de-la-Vega-Monroy, Maria-Luisa, Karen-Alejandra Mata-Tapia, Juan-Antonio Garcia-Santillan, Maria-Angelica Corona-Figueroa, Martha-Isabel Gonzalez-Dominguez, Hector-Manuel Gomez-Zapata, Juan-Manuel Malacara, Leonel Daza-Benitez, and Gloria Barbosa-Sabanero. "Association of placental nutrient sensing pathways with birth weight." Reproduction 160, no. 3 (September 2020): 455–68. http://dx.doi.org/10.1530/rep-20-0186.

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Birth weight (BW) is an important indicator for newborn health. Both high and low BW is associated with increased risks for adult metabolic diseases. AMPK (AMP-activated protein kinase), mTOR (mechanistic target of rapamycin), and insulin/IGF1 (insulin-like growth factor 1) pathways may function as placental sensors of maternal hormonal and nutritional status. However, the physiological role of these pathways in placenta has not been completely elucidated. To evaluate expression and activation of AMPK, mTOR, and insulin/IGF1 pathways and its association with placental weight (PW), BW, and maternal hormonal and metabolic status, we performed a cross-sectional study in placentas from non-obese mothers with SGA (n = 17), AGA (n = 19) and LGA (n = 10) newborns. We analyzed placental expression of total and phosphorylated key proteins from the AMPK, mTOR and insulin/IGF1 pathways. Maternal and cord blood hormones were determined by ELISA. AMPK and LKB1 activation correlated negatively with PW and BW, cord leptin, and pregestational BMI. Placental SIRT1 inversely correlated with BW, cord leptin, neonatal HOMA-IR, and maternal IGF1. PGC1α correlated negatively with PW and BW. Phosphorylated mTOR positively correlated with maternal glucose, PW and BW. IGF1R was lower in SGA. No changes in p-IGF1R, INSRb, total AKT or p-AKT were found, and pPDK1 was lower in SGA and LGA. These results suggest that placental AMPK, insulin/IGF1, and mTOR pathways may influence fetal growth, perhaps regulating placental physiology, even in metabolically healthy pregnancies. Our study highlights these nutrient sensing pathways as potential molecular mechanisms modulating placental adaptations and, thus, long-term metabolic health.

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Ávalos, Yenniffer, Jimena Canales, Roberto Bravo-Sagua, Alfredo Criollo, Sergio Lavandero, and Andrew F. G. Quest. "Tumor Suppression and Promotion by Autophagy." BioMed Research International 2014 (2014): 1–15. http://dx.doi.org/10.1155/2014/603980.

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Autophagy is a highly regulated catabolic process that involves lysosomal degradation of proteins and organelles, mostly mitochondria, for the maintenance of cellular homeostasis and reduction of metabolic stress. Problems in the execution of this process are linked to different pathological conditions, such as neurodegeneration, aging, and cancer. Many of the proteins that regulate autophagy are either oncogenes or tumor suppressor proteins. Specifically, tumor suppressor genes that negatively regulate mTOR, such as PTEN, AMPK, LKB1, and TSC1/2 stimulate autophagy while, conversely, oncogenes that activate mTOR, such as class I PI3K, Ras, Rheb, and AKT, inhibit autophagy, suggesting that autophagy is a tumor suppressor mechanism. Consistent with this hypothesis, the inhibition of autophagy promotes oxidative stress, genomic instability, and tumorigenesis. Nevertheless, autophagy also functions as a cytoprotective mechanism under stress conditions, including hypoxia and nutrient starvation, that promotes tumor growth and resistance to chemotherapy in established tumors. Here, in this brief review, we will focus the discussion on this ambiguous role of autophagy in the development and progression of cancer.

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Tanwar, Pradeep S., Tomoko Kaneko-Tarui, LiHua Zhang, and Jose M. Teixeira. "Altered LKB1/AMPK/TSC1/TSC2/mTOR signaling causes disruption of Sertoli cell polarity and spermatogenesis." Human Molecular Genetics 21, no. 20 (July 12, 2012): 4394–405. http://dx.doi.org/10.1093/hmg/dds272.

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Liemburg-Apers, Dania C., Jori A. L. Wagenaars, Jan A. M. Smeitink, Peter H. G. M. Willems, and Werner J. H. Koopman. "Acute stimulation of glucose influx upon mitoenergetic dysfunction requires LKB1, AMPK, Sirt2 and mTOR–RAPTOR." Journal of Cell Science 129, no. 23 (October 28, 2016): 4411–23. http://dx.doi.org/10.1242/jcs.194480.

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Vila-Bedmar, Rocio, Margarita Lorenzo, and Sonia Fernández-Veledo. "Adenosine 5′-Monophosphate-Activated Protein Kinase-Mammalian Target of Rapamycin Cross Talk Regulates Brown Adipocyte Differentiation." Endocrinology 151, no. 3 (February 4, 2010): 980–92. http://dx.doi.org/10.1210/en.2009-0810.

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Brown adipose tissue (BAT) is considered of metabolic significance in mammalian physiology, because it plays an important role in regulating energy balance. Alterations in this tissue have been associated with obesity and type 2 diabetes. The molecular mechanisms modulating brown adipocyte differentiation are not fully understood. Using a murine brown preadipocyte cell line, primary cultures, and 3T3-L1 cells, we analyzed the contribution of various intracellular signaling pathways to adipogenic and thermogenic programs. Sequential activation of p38MAPK and LKB1-AMPK-tuberous sclerosis complex 2 (TSC2) as well as significant attenuation of ERK1/2 and mammalian target of rapamycin (mTOR)-p70 S6 kinase 1 (p70S6K1) activation was observed through the brown differentiation process. This study demonstrates a critical role for AMPK in controlling the mTOR-p70S6K1 signaling cascade in brown but not in 3T3-L1 adipocytes. We observed that mTOR activity is essential in the first stages of differentiation. Nevertheless, subsequent inhibition of this cascade by AMPK activation is also necessary at later stages. An in vivo study showed that prolonged 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR)-induced AMPK activation increases uncoupling protein 1 expression and induces an accumulation of brown adipocytes in white adipose tissue (WAT), as revealed by immunohistology. Moreover, the induction of brown adipogenesis in areas of white fat partially correlates with the body weight reduction detected in response to treatment with AICAR. Taken together, our study reveals that differentiation of brown adipocytes employs different signaling pathways from white adipocytes, with AMPK-mTOR cross talk a central mediator of this process. Promotion of BAT development in WAT by pharmacological activation of AMPK may have potential in treating obesity by acting on energy dissipation.

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Shackelford, D. B., D. S. Vasquez, J. Corbeil, S. Wu, M. Leblanc, C. L. Wu, D. R. Vera, and R. J. Shaw. "mTOR and HIF-1 -mediated tumor metabolism in an LKB1 mouse model of Peutz-Jeghers syndrome." Proceedings of the National Academy of Sciences 106, no. 27 (June 18, 2009): 11137–42. http://dx.doi.org/10.1073/pnas.0900465106.

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Dong, Li-xia, Lin-lin Sun, Xia Zhang, Li Pan, Lin-juan Lian, Zhe Chen, and Dian-sheng Zhong. "Negative regulation of mTOR activity by LKB1-AMPK signaling in non-small cell lung cancer cells." Acta Pharmacologica Sinica 34, no. 2 (November 26, 2012): 314–18. http://dx.doi.org/10.1038/aps.2012.143.

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Wildenberg, Manon, Anne Christine Vos, Marjolijn Duijvestein, Auke P. Verhaar, Daniel W. Hommes, and Gijs R. van den Brink. "Tu1945 Induction of Autophagy Upon DC-T Cell Contact is Mediated by LKB1-AMPK-mTOR Signalling." Gastroenterology 142, no. 5 (May 2012): S—884. http://dx.doi.org/10.1016/s0016-5085(12)63432-5.

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Wildenberg, M. E., A. C. Vos, M. Duijvestein, A. Verhaar, G. van den Brink, and D. W. Hommes. "OP03 Induction of autophagy upon DC-T cell contact is mediated by LKB1 AMPK mTOR signalling." Journal of Crohn's and Colitis 6 (February 2012): S2. http://dx.doi.org/10.1016/s1873-9946(12)60004-x.

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Han, Jie, Huimin Liang, Derun Tian, Jianying Du, Qiming Wang, Pengjiao Xi, Haomin Wang, and Yongmei Li. "mTOR remains unchanged in diet-resistant (DR) rats despite impaired LKB1/AMPK cascade in adipose tissue." Biochemical and Biophysical Research Communications 476, no. 4 (August 2016): 333–39. http://dx.doi.org/10.1016/j.bbrc.2016.05.123.

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Borthakur, Gautam, Michael Andreeff, Kevin R. Coombes, Yi Hua Qiu, Seshagiri Duvvuri, Nianxiang Zhang, Vivian Ruvolo, et al. "High Expression of Autophagy Related Proteins Negatively Impacts Clinical Outcomes in Acute Myelogenous Leukemia–Time to Target Autophagy to Improve Therapy Outcomes?" Blood 118, no. 21 (November 18, 2011): 2513. http://dx.doi.org/10.1182/blood.v118.21.2513.2513.

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Abstract Abstract 2513 Background: Autophagy, like apoptosis is a programmed cell death pathway that can be pharmacologically targeted. Apoptosis and autophagy pathways interact at the level of Bcl-2 family of proteins. Autophagy helps transformed cells to survive hypoxia, nutrient lack and chemotherapeutic stress. While expressions of pro/anti-apoptotic genes/proteins in acute myelogenous leukemia (AML) blasts have been linked to clinical outcome (Kornblau et al. Clin. Cancer Res 1999; 5:1758, Hess et al. JCO 2007;10:1209, Carter et al. Blood 2011;117:1280), the expression of autophagy related proteins (ARP) in primary AML cells and their impact on prognosis in AML has not been reported. Methods: Quantitative expression of ARP in blast cells from 511 patients with newly diagnosed AML (divided into 3 cytogenetic risk groups) was determined by reverse phase protein array (RPPA). Analysis used unbiased clustering, perturbation bootstrap clustering, and principle component analysis. The values for ARP were divided into thirds (low, medium, and high cohorts) based on the range of expression of all 500 samples. Kaplan-Meier product limit method was used to generate overall survival (OS) and complete remission duration (CRD) curves and log-rank test was used to assess the difference between patients with high and low expressions of ARP. Univariate and multivariate (MVA) Cox proportional hazard modeling included clinical and laboratory parameters relevant to AML outcome (categorized or continuous) and protein levels as categorized variables. We also correlated expression of ARP with 186 other proteins (encompassing signal transduction, metabolism, apoptosis pathways) that were included in RPPA. Results: ARP analyzed by RPPA included Beclin1, LKB1, phospho and total AMPK and p62. While Beclin 1 and p62 are proteins integral to autophagosome development and ‘cargo’ delivery to autophagosome, LKB1 and AMPK are kinases upstream of autophagy initiation. Beclin 1 also has dual role in apoptosis and autophagy; caspase mediated cleavage of Beclin 1 suppresses autophagy and enhances apoptosis. Among all patients with AML, high LKB1 expression (higher 2/3rd versus lower 1/3rd) was associated with significantly shorter OS (p=.037) (Fig. 1). MVA identified higher age, poor-risk cytogenetics, high WBC, low platelet count, low albumin and high LKB1 (p=.01) as variables associated with shorter OS. High expression of Beclin1 (high 1/3rd vs lower 2/3rd) was associated with a trend towards worse OS (p=.07) and significantly associated with shorter CRD(p=.0009) (Fig. 2) among patients with intermediate cytogenetic risk AML (AML-IR). This impact on CRD was seen regardless of FLT3-ITD mutation status. By MVA older age, FLT3-ITD mutation, high Beclin1 (p=.019 for Beclin1) were significantly associated with shorter OS, while age, FLT3-ITD and high Beclin 1 expression (p=.0009 for Beclin 1) were significantly associated with shorter CR among patients with AML-IR. Finally, RPPA analysis restricted to CD34+cells showed highest expression of LKB1 in CD34+CD38-AML “progenitor cell” population (p=0.0000). Expression of Beclin1 in AML cells correlated positively with Akt, mTOR, PTEN, SHIP2, TSC2, PP2A, JNK2, TAZ etc. and negatively p53, p21, Bcl-XL, HIF1 alpha, FOXO3a etc. LKB1 expression correlated positively with GSK3β, DJ1, TSC2, NFKBp65, PI3Kp110, XIAP, HSP90 etc. and negatively with FOXO3a, Bcl-2, BADp112, AIF etc. Conclusion: This is the first report of prognostic impact of autophagy related protein expression in AML and their correlation with proteins of other pathways. High expression of LKB1 and Beclin1 were found to be associated with poor clinical outcome. Highest expression of LKB1 is seen in AML “progenitor” cells. Results suggest that targeting of autophagy regulators may have clinical utility in AML therapy. Integration of ARP expression data in to cellular pathways is in progress. Grant support: ASCO Career Development Award (GB) and CA55164 from NIH(MA) Disclosures: Borthakur: ASCO Career Development Award: Research Funding. Andreeff:NIH CA55164: Research Funding.

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Hou, Yawei, Yameng Li, Yichuan Wang, Wenpu Li, and Zhenwei Xiao. "Screening and Analysis of Key Genes in miRNA-mRNA Regulatory Network of Membranous Nephropathy." Journal of Healthcare Engineering 2021 (November 16, 2021): 1–13. http://dx.doi.org/10.1155/2021/5331948.

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Background. MicroRNAs (miRNAs) are confirmed to participate in occurrence, development, and prevention of membranous nephropathy (MN), but their mechanism of action is unclear. Objective. With the GEO database and the use of bioinformatics, miRNA-mRNA regulatory network genes relevant to MN were explored and their potential mechanism of action was explained. Methods. The MN-related miRNA chip data set (GSE51674) and mRNA chip data set (GSE108109) were downloaded from the GEO database. Differential analysis was performed using the GEO2R online tool. TargetScan, miRTarBase, and StarBase databases were used to predict potential downstream target genes regulated by differentially expressed miRNAs, and the intersection with differential genes were taken to obtain candidate target genes. According to the regulatory relationship between miRNA and mRNA, the miRNA-mRNA relationship pair was clarified and Cytoscape was used to construct a miRNA-mRNA regulatory network. WebGestalt was used to conduct enrichment analysis of the biological process of differential mRNAs in the regulatory network; FunRich analyzes the differential mRNA pathways in the miRNA-mRNA regulatory network. And the STRING database was used to construct a PPI network for candidate target genes, and Cytoscape visually analyzes the PPI network. Results. Experiments were conducted to screen differentially expressed miRNAs and mRNAs. There were 30 differentially expressed miRNAs, including 22 upregulated and 8 downregulated; and 1267 differentially expressed mRNAs, including 536 upregulated and 731 downregulated. Using TargetScan, miRTarBase, and StarBase databases to predict the downstream targets of differentially expressed miRNAs, 2957 downstream target genes coexisting in the 3 databases were predicted to intersect with differentially expressed mRNAs to obtain 175 candidate target genes. Finally, 36 miRNA-mRNA relationship pairs comprising 10 differentially expressed miRNAs and 27 differentially expressed mRNAs were screened out, and the regulatory network was constructed. Further analysis revealed that the miRNA regulatory network genes may be involved in the development of membranous nephropathy by mTOR, PDGFR-β, LKB1, and VEGF/VEGFR signaling pathways. Conclusion. The miRNA regulatory network genes may participate in the regulation of podocyte autophagy, lipid metabolism, and renal fibrosis through mTOR, PDGFR-β, LKB1, and VEGF/VEGFR signaling pathways, thereby affecting the occurrence and development of membranous nephropathy.

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Goel, MadhuMati, Annu Makker, AbbasAli Mahdi, Vikram Bhatia, Vinita Das, Anjoo Agarwal, and Amita Pandey. "PI3K/Akt/mTOR signaling & its regulator tumour suppressor genes PTEN & LKB1 in human uterine leiomyomas." Indian Journal of Medical Research 143, no. 7 (2016): 112. http://dx.doi.org/10.4103/0971-5916.191808.

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Nguyen, H. B., J. T. Babcock, C. D. Wells, and L. A. Quilliam. "LKB1 tumor suppressor regulates AMP kinase/mTOR-independent cell growth and proliferation via the phosphorylation of Yap." Oncogene 32, no. 35 (October 1, 2012): 4100–4109. http://dx.doi.org/10.1038/onc.2012.431.

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Lai, L. P., B. N. Lilley, J. R. Sanes, and A. P. McMahon. "Lkb1/Stk11 regulation of mTOR signaling controls the transition of chondrocyte fates and suppresses skeletal tumor formation." Proceedings of the National Academy of Sciences 110, no. 48 (November 11, 2013): 19450–55. http://dx.doi.org/10.1073/pnas.1309001110.

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Journal articles on the topic 'LKB1/mTOR'

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