Journal articles: 'HSC70; Cancer'

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Mahboubi, Hicham, and Ursula Stochaj. "Quantitative analysis of the interplay between hsc70 and its co-chaperone HspBP1." PeerJ 3 (December 21, 2015): e1530. http://dx.doi.org/10.7717/peerj.1530.

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Background.Chaperones and their co-factors are components of a cellular network; they collaborate to maintain proteostasis under normal and harmful conditions. In particular, hsp70 family members and their co-chaperones are essential to repair damaged proteins. Co-chaperones are present in different subcellular compartments, where they modulate chaperone activities.Methods and Results.Our studies assessed the relationship between hsc70 and its co-factor HspBP1 in human cancer cells. HspBP1 promotes nucleotide exchange on hsc70, but has also chaperone-independent functions. We characterized the interplay between hsc70 and HspBP1 by quantitative confocal microscopy combined with automated image analyses and statistical evaluation. Stress and the recovery from insult changed significantly the subcellular distribution of hsc70, but had little effect on HspBP1. Single-cell measurements and regression analysis revealed that the links between the chaperone and its co-factor relied on (i) the physiological state of the cell and (ii) the subcellular compartment. As such, we identified a linear relationship and strong correlation between hsc70 and HspBP1 distribution in control and heat-shocked cells; this correlation changed in a compartment-specific fashion during the recovery from stress. Furthermore, we uncovered significant stress-induced changes in the colocalization between hsc70 and HspBP1 in the nucleus and cytoplasm.Discussion.Our quantitative approach defined novel properties of the co-chaperone HspBP1 as they relate to its interplay with hsc70. We propose that changes in cell physiology promote chaperone redistribution and thereby stimulate chaperone-independent functions of HspBP1.

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Oda, Tsukasa, Hidenobu Miyaso, and Takayuki Yamashita. "Nuclear Localization of Fanconi Anemia Protein FANCA Is Regulated by Hsc70/Hsp90 Chaperone Machinery." Blood 104, no. 11 (November 16, 2004): 2835. http://dx.doi.org/10.1182/blood.v104.11.2835.2835.

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Abstract Fanconi anemia (FA) is a genetic disorder characterized by bone marrow failure, cancer susceptibility and cellular hypersensitivity to DNA crosslinkers such as mitomycin C (MMC). Current evidence indicates that formation of a nuclear multiprotein complex (core complex) including six FA proteins FANCA/C/E/F/G/L is essential for FANCL/PHF9 ubiquitin ligase-mediated activation of FANCD2 into a monoubiquinated form, which participates in BRCA1 and FANCD1/BRCA2-mediated DNA repair (the FA/BRCA pathway). Subcellular distribution of FANCA plays a crucial role in the regulation of the FA/BRCA pathway. However, the underlying molecular mechanisms are not fully understood. To address this issue, we tried to identify FANCA-associated proteins. To this end, Flag-FANCA ectopically expressed in HeLa cells was immunopurified from the cytoplasmic fraction, using anti-Flag antibody-conjugated sepharose beads. Analysis of the immune complex on SDS polyacrylamide gel electrophoresis revealed that several proteins of Mr. 60–70 kD specifically associated with Flag-FANCA. These proteins were identified as FANCG and Hsc (heat shock cognate protein) 70 by LC-MS/MS. Immunoblot analysis showed that FANCA associated with Hsp90 as well as Hsc70. Hsc70 is an ATP-dependent molecular chaperone highly homologous to Hsp70 and often cooperates with Hsp90 to form a chaperone machinery involved in the regulation of diverse protein functions. Patient-derived FANCA mutants failed to bind FANCC but associated with larger amounts of Hsc70 than wt-FANCA, indicating that the interaction between FANCA and Hsc70 is not mediated by FANCC, as suggested by previous observations of the interaction of FANCC with Hsp70. To study the role of Hsc70 and Hsp90 in the regulation of FANCA, we examined effects of a dominant-negative (dn) form of Hsc70 with inactivated ATPase activity, and a specific inhibitor of Hsp90, 17-AAG (a geldanamycin analog). Overexpression of dn-Hsc70 inhibited nuclear localization of FANCA and inhibited its core complex formation, whereas wt-Hsc70 did not. 17-AAG induced cytoplasmic distribution and proteosomal degradation of FANCA and suppressed FANCD2 mono-ubiquitination. Taken together, these results suggest that Hsc70/Hsp90 chaperone machinery interacts with FANCA and regulates its subcellular distribution and stability, thereby controlling activation of the FA/BRCA pathway.

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Luan, Haitao, Tameka A. Bailey, Robert J. Clubb, Bhopal C. Mohapatra, Aaqib M. Bhat, Sukanya Chakraborty, Namista Islam, et al. "CHIP/STUB1 Ubiquitin Ligase Functions as a Negative Regulator of ErbB2 by Promoting Its Early Post-Biosynthesis Degradation." Cancers 13, no. 16 (August 4, 2021): 3936. http://dx.doi.org/10.3390/cancers13163936.

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Overexpression of the epidermal growth factor receptor (EGFR) family member ErbB2 (HER2) drives oncogenesis in up to 25% of invasive breast cancers. ErbB2 expression at the cell surface is required for oncogenesis but mechanisms that ensure the optimal cell surface display of overexpressed ErbB2 following its biosynthesis in the endoplasmic reticulum are poorly understood. ErbB2 is dependent on continuous association with HSP90 molecular chaperone for its stability and function as an oncogenic driver. Here, we use knockdown and overexpression studies to show that the HSP90/HSC70-interacting negative co-chaperone CHIP (C-terminus of HSC70-Interacting protein)/STUB1 (STIP1-homologous U-Box containing protein 1) targets the newly synthesized, HSP90/HSC70-associated, ErbB2 for ubiquitin/proteasome-dependent degradation in the endoplasmic reticulum and Golgi, thus identifying a novel mechanism that negatively regulates cell surface ErbB2 levels in breast cancer cells, consistent with frequent loss of CHIP expression previously reported in ErbB2-overexpressing breast cancers. ErbB2-overexpressing breast cancer cells with low CHIP expression exhibited higher endoplasmic reticulum stress inducibility. Accordingly, the endoplasmic reticulum stress-inducing anticancer drug Bortezomib combined with ErbB2-targeted humanized antibody Trastuzumab showed synergistic inhibition of ErbB2-overexpressing breast cancer cell proliferation. Our findings reveal new insights into mechanisms that control the surface expression of overexpressed ErbB2 and suggest that reduced CHIP expression may specify ErbB2-overexpressing breast cancers suitable for combined treatment with Trastuzumab and ER stress inducing agents.

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DeGeer, Jonathan, Andrew Kaplan, Pierre Mattar, Morgane Morabito, Ursula Stochaj, Timothy E. Kennedy, Anne Debant, Michel Cayouette, Alyson E. Fournier, and Nathalie Lamarche-Vane. "Hsc70 chaperone activity underlies Trio GEF function in axon growth and guidance induced by netrin-1." Journal of Cell Biology 210, no. 5 (August 31, 2015): 817–32. http://dx.doi.org/10.1083/jcb.201505084.

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During development, netrin-1 is both an attractive and repulsive axon guidance cue and mediates its attractive function through the receptor Deleted in Colorectal Cancer (DCC). The activation of Rho guanosine triphosphatases within the extending growth cone facilitates the dynamic reorganization of the cytoskeleton required to drive axon extension. The Rac1 guanine nucleotide exchange factor (GEF) Trio is essential for netrin-1–induced axon outgrowth and guidance. Here, we identify the molecular chaperone heat shock cognate protein 70 (Hsc70) as a novel Trio regulator. Hsc70 dynamically associated with the N-terminal region and Rac1 GEF domain of Trio. Whereas Hsc70 expression supported Trio-dependent Rac1 activation, adenosine triphosphatase–deficient Hsc70 (D10N) abrogated Trio Rac1 GEF activity and netrin-1–induced Rac1 activation. Hsc70 was required for netrin-1–mediated axon growth and attraction in vitro, whereas Hsc70 activity supported callosal projections and radial neuronal migration in the embryonic neocortex. These findings demonstrate that Hsc70 chaperone activity is required for Rac1 activation by Trio and this function underlies netrin-1/DCC-dependent axon outgrowth and guidance.

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Chernikov, V. A., N. V. Gorokhovets, L. V. Savvateeva, and S. E. Severin. "Analysis of complex formation of human recombinant hsp70 with tumor-associated peptides." Biomeditsinskaya Khimiya 58, no. 6 (2012): 651–61. http://dx.doi.org/10.18097/pbmc20125806651.

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Molecular chaperones of HSP70 family assists presentation of exogenous antigenic peptides by antigen-presenting cells (APC). HSP70-peptide complexes are powerful immunotherapeutic agents, which enhance cross-presentation of captured antigen in dendritic cells and macrophages. Several clinical trials have shown that HSP-based cancer vaccines possess good efficacy and safety. However, sometime it is impossible to isolate sufficient amount of vaccine. These make us to pay attention for recombinant HSP70-based vaccines and to optimize in vitro complex formation mechanism. Here we have investigated two human recombinant proteins HSP70HYB and HSC70. Optimal values of ADP concentration, pH, temperature and peptides excess are determined in this work. We have also shown that proposed complex formation method enriches eluted from HSP70-complexes peptide repertoire compared to in vivo assembled ones.

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Tan, Aik-Aun, Wai-Mei Phang, Subash C. B. Gopinath, Onn H. Hashim, Lik Voon Kiew, and Yeng Chen. "Revealing Glycoproteins in the Secretome of MCF-7 Human Breast Cancer Cells." BioMed Research International 2015 (2015): 1–8. http://dx.doi.org/10.1155/2015/453289.

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Breast cancer is one of the major issues in the field of oncology, reported with a higher prevalence rate in women worldwide. In attempt to reveal the potential biomarkers for breast cancer, the findings of differentially glycosylated haptoglobin and osteonectin in previous study have drawn our attention towards glycoproteins of secretome from the MCF-7 cancer cell line. In the present study, further analyses were performed on the medium of MCF-7 cells by subjecting it to two-dimensional analyses followed by image analysis in contrast to the medium of human mammary epithelial cells (HMEpC) as a negative control. Carboxypeptidase A4 (CPA4), alpha-1-antitrypsin (AAT), haptoglobin (HP), and HSC70 were detected in the medium of MCF-7, while only CPA4 and osteonectin (ON) were detected in HMEpC medium. In addition, CPA4 was detected as upregulated in the MCF-7 medium. Further analysis by lectin showed that CPA4, AAT, HP, and HSC70 were secreted as N-glycan in the medium of MCF-7, with HP also showing differentially N-glycosylated isoforms. For the HMEpC, only CPA4 was detected as N-glycan. No O-glycan was detected in the medium of HMEpC but MCF-7 expressed O-glycosylated CPA4 and HSC70. All these revealed that glycoproteins could be used as glycan-based biomarkers for the prognosis of breast cancer.

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Dublang, Leire, Jarl Underhaug, Marte I. Flydal, Lorea Velasco-Carneros, Jean-Didier Maréchal, Fernando Moro, Maria Dolores Boyano, Aurora Martinez, and Arturo Muga. "Inhibition of the Human Hsc70 System by Small Ligands as a Potential Anticancer Approach." Cancers 13, no. 12 (June 11, 2021): 2936. http://dx.doi.org/10.3390/cancers13122936.

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Heat shock protein (Hsp) synthesis is upregulated in a wide range of cancers to provide the appropriate environment for tumor progression. The Hsp110 and Hsp70 families have been associated to cancer cell survival and resistance to chemotherapy. In this study, we explore the strategy of drug repurposing to find new Hsp70 and Hsp110 inhibitors that display toxicity against melanoma cancer cells. We found that the hits discovered using Apg2, a human representative of the Hsp110 family, as the initial target bind also to structural regions present in members of the Hsp70 family, and therefore inhibit the remodeling activity of the Hsp70 system. One of these compounds, the spasmolytic agent pinaverium bromide used for functional gastrointestinal disorders, inhibits the intracellular chaperone activity of the Hsp70 system and elicits its cytotoxic activity specifically in two melanoma cell lines by activating apoptosis. Docking and molecular dynamics simulations indicate that this compound interacts with regions located in the nucleotide-binding domain and the linker of the chaperones, modulating their ATPase activity. Thus, repurposing of pinaverium bromide for cancer treatment appears as a promising novel therapeutic approach.

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Kobayashi, Yukino, Ami Oguro, Yuta Hirata, and Susumu Imaoka. "The regulation of Hypoxia-Inducible Factor-1 (HIF-1alpha) expression by Protein Disulfide Isomerase (PDI)." PLOS ONE 16, no. 2 (February 4, 2021): e0246531. http://dx.doi.org/10.1371/journal.pone.0246531.

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Hypoxia-inducible factor-1alpha (HIF-1alpha), a transcription factor, plays a critical role in adaption to hypoxia, which is a major feature of diseases, including cancer. Protein disulfide isomerase (PDI) is up-regulated in numerous cancers and leads to cancer progression. PDI, a member of the TRX superfamily, regulates the transcriptional activities of several transcription factors. To investigate the mechanisms by which PDI affects the function of HIF-1alpha, the overexpression or knockdown of PDI was performed. The overexpression of PDI decreased HIF-1alpha expression in the human hepatocarcinoma cell line, Hep3B, whereas the knockdown of endogenous PDI increased its expression. NH4Cl inhibited the decrease in HIF-1alpha expression by PDI overexpression, suggesting that HIF-1alpha was degraded by the lysosomal pathway. HIF-1alpha is transferred to lysosomal membranes by heat shock cognate 70 kDa protein (HSC70). The knockdown of HSC70 abolished the decrease, and PDI facilitated the interaction between HIF-1alpha and HSC70. HIF-1alpha directly interacted with PDI. PDI exists not only in the endoplasmic reticulum (ER), but also in the cytosol. Hypoxia increased cytosolic PDI. We also investigated changes in the redox state of HIF-1alpha using PEG-maleimide, which binds to thiols synthesized from disulfide bonds by reduction. An up-shift in the HIF-1alpha band by the overexpression of PDI was detected, suggesting that PDI formed disulfide bond in HIF-1alpha. HIF-1alpha oxidized by PDI was not degraded in HSC70-knockdown cells, indicating that the formation of disulfide bond in HIF-1alpha was important for decreases in HIF-1alpha expression. To the best of our knowledge, this is the first study to show the regulation of the expression and redox state of HIF-1alpha by PDI. We also demonstrated that PDI formed disulfide bonds in HIF-1alpha 1–245 aa and decreased its expression. In conclusion, the present results showed that PDI is a novel factor regulating HIF-1alpha through lysosome-dependent degradation by changes in its redox state.

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Doong, Howard, John Price, Young Sook Kim, Christopher Gasbarre, Julie Probst, Lance A. Liotta, Jay Blanchette, Kathryn Rizzo, and Elise Kohn. "CAIR-1/BAG-3 forms an EGF-regulated ternary complex with phospholipase C-γ and Hsp70/Hsc70." Oncogene 19, no. 38 (September 2000): 4385–95. http://dx.doi.org/10.1038/sj.onc.1203797.

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Tanaka, Masako, Saya Mun, Akihito Harada, Yasuyuki Ohkawa, Azusa Inagaki, Soichi Sano, Katsuyuki Takahashi, et al. "Hsc70 Contributes to Cancer Cell Survival by Preventing Rab1A Degradation under Stress Conditions." PLoS ONE 9, no. 5 (May 6, 2014): e96785. http://dx.doi.org/10.1371/journal.pone.0096785.

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Choi, Ye Na, Sun Kyung Lee, Tae Woong Seo, Ji Sun Lee, and Soon Ji Yoo. "C-terminus of Hsc70-interacting protein regulates profilin1 and breast cancer cell migration." Biochemical and Biophysical Research Communications 446, no. 4 (April 2014): 1060–66. http://dx.doi.org/10.1016/j.bbrc.2014.03.061.

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Wang, Bo-Shi, Yang Yang, Hai Yang, Yi-Zhen Liu, Jia-Jie Hao, Yu Zhang, Zhi-Zhou Shi, Xue-Mei Jia, Qi-Min Zhan, and Ming-Rong Wang. "PKCι counteracts oxidative stress by regulating Hsc70 in an esophageal cancer cell line." Cell Stress and Chaperones 18, no. 3 (December 9, 2012): 359–66. http://dx.doi.org/10.1007/s12192-012-0389-4.

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Iwanaga, Masashi, Yuka Shibano, Takeshi Ohsawa, Takako Fujita, Susumu Katsuma, and Hideki Kawasaki. "Involvement of HSC70-4 and other inducible HSPs in Bombyx mori nucleopolyhedrovirus infection." Virus Research 179 (January 2014): 113–18. http://dx.doi.org/10.1016/j.virusres.2013.10.028.

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Kang, Shin-Ae, Hyun-Soo Cho, Jong Bok Yoon, In Kwon Chung, and Seung-Taek Lee. "Hsp90 rescues PTK6 from proteasomal degradation in breast cancer cells." Biochemical Journal 447, no. 2 (September 26, 2012): 313–20. http://dx.doi.org/10.1042/bj20120803.

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PTK6 [protein tyrosine kinase 6; also known as Brk (breast tumour kinase)] is a non-receptor tyrosine kinase, closely related to Src, but evolutionarily distinct, that is up-regulated in various cancers, including breast cancer. Hsp90 (heat-shock protein 90) was identified as a PTK6-interacting protein in HEK (human embryonic kidney)-293 cells overexpressing PTK6. Hsp90 interacted with the PTK6 tyrosine kinase catalytic domain, but catalytic activity was not required for the interaction. Geldanamycin, an Hsp90 inhibitor, significantly decreased the PTK6 protein level through proteasome-dependent degradation, but did not affect the level of Src. Geldanamycin treatment also decreased phosphorylation of PTK6 substrates due to reduced amounts of PTK6. Moreover, overexpression of CHIP [C-terminus of Hsc70 (heat-shock cognate 70)-interacting protein], a chaperone-dependent E3 ligase, enhanced proteosomal degradation of PTK6. Geldanamycin increased the interaction of PTK6 with CHIP, but decreased the interaction of PTK6 with Hsp90. We also found that endogenous PTK6 associated with Hsp90 and geldanamycin decreased expression of endogenous PTK6 in breast carcinoma cells. Finally, we report that silencing endogenous CHIP expression in breast carcinoma cells inhibited geldanamycin-induced PTK6 reduction. These results demonstrate that Hsp90 plays an essential role in regulating PTK6 stability and suggest that Hsp90 inhibitors may be useful as therapeutic drugs for PTK6-positive cancers, including breast cancer.

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Xiao, Meng, Ming Yan, Jianjun Zhang, Qin Xu, and Wantao Chen. "Carboxy-terminus Hsc70 interacting protein exerts a tumor inhibition function in head and neck cancer." Oncology Reports 38, no. 3 (March 2017): 1629–36. http://dx.doi.org/10.3892/or.2017.5827.

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Wang, Hang-Hui, Yi-Xin Song, Min Bai, Li-Fang Jin, Ji-Ying Gu, Yi-Jin Su, Long Liu, Chao Jia, and Lian-Fang Du. "Ultrasound Targeted Microbubble Destruction for Novel Dual Targeting of HSP72 and HSC70 in Prostate Cancer." Asian Pacific Journal of Cancer Prevention 15, no. 3 (February 1, 2014): 1285–90. http://dx.doi.org/10.7314/apjcp.2014.15.3.1285.

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Moghanibashi, Mehdi, Ferdous Rastgar Jazii, Zahra-Soheila Soheili, Maryam Zare, Aliasghar Karkhane, Kazem Parivar, and Parisa Mohamadynejad. "Esophageal cancer alters the expression of nuclear pore complex binding protein Hsc70 and eIF5A-1." Functional & Integrative Genomics 13, no. 2 (March 29, 2013): 253–60. http://dx.doi.org/10.1007/s10142-013-0320-9.

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Powers, Marissa V., Paul A. Clarke, and Paul Workman. "Dual Targeting of HSC70 and HSP72 Inhibits HSP90 Function and Induces Tumor-Specific Apoptosis." Cancer Cell 14, no. 3 (September 2008): 250–62. http://dx.doi.org/10.1016/j.ccr.2008.08.002.

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Chen, Jinyun, Yujie Yang, Wade A. Russu, and William K. Chan. "The Aryl Hydrocarbon Receptor Undergoes Chaperone-Mediated Autophagy in Triple-Negative Breast Cancer Cells." International Journal of Molecular Sciences 22, no. 4 (February 6, 2021): 1654. http://dx.doi.org/10.3390/ijms22041654.

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The aryl hydrocarbon receptor (AHR) is a ligand-activated signaling molecule expressed in many cell types, including triple-negative and non-triple-negative breast cancer cells. It affects breast cancer growth and crosstalk with estrogen receptor signaling. Normally, this receptor is degraded shortly after ligand activation via the 26S proteasome. Here, we report that AHR undergoes chaperone-mediated autophagy in MDA-MB-468 triple-negative breast cancer cells. This lysosomal degradation of AHR exhibits the following characteristics: (1) it is triggered by 6 amino-nicotinamide, starvation, and piperazinylpyrimidine compound Q18; (2) it is not observed in non-triple-negative breast cancer cells (MCF-7, T47D, and MDA-MB-361); (3) it can be inhibited by progesterone receptor B but not estrogen receptor alpha; (4) it can be reversed by chloroquine but not MG132; (5) it requires LAMP2A; and (6) it involves AHR-HSC70 and AHR-LAMP2A interactions. The NEKFF sequence localized at amino acid 558 of human AHR appears to be a KFERQ-like motif of chaperone-mediated autophagy, responsible for the LAMP2A-mediated AHR protein degradation.

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Liu, Tuoen, Ratan Singh, Zechary Rios, Alok Bhushan, Mengxiong Li, Peter P. Sheridan, Shawn E. Bearden, et al. "Tyrosine phosphorylation of HSC70 and its interaction with RFC mediates methotrexate resistance in murine L1210 leukemia cells." Cancer Letters 357, no. 1 (February 2015): 231–41. http://dx.doi.org/10.1016/j.canlet.2014.11.036.

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Chandra, Vishal, Rajani Rai, and Doris Mangiaracina Benbrook. "Utility and Mechanism of SHetA2 and Paclitaxel for Treatment of Endometrial Cancer." Cancers 13, no. 10 (May 12, 2021): 2322. http://dx.doi.org/10.3390/cancers13102322.

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Endometrial cancer patients with advanced disease or high recurrence risk are treated with chemotherapy. Our objective was to evaluate the utility and mechanism of a novel drug, SHetA2, alone and in combination with paclitaxel, in endometrial cancer. SHetA2 targets the HSPA chaperone proteins, Grp78, hsc70, and mortalin, which have high mutation rates in endometrial cancer. SHetA2 effects on cancerous phenotypes, mitochondria, metabolism, protein expression, mortalin/client protein complexes, and cell death were evaluated in AN3CA, Hec13b, and Ishikawa endometrial cancer cell lines, and on growth of Ishikawa xenografts. In all three cell lines, SHetA2 inhibited anchorage-independent growth, migration, invasion, and ATP production, and induced G1 cell cycle arrest, mitochondrial damage, and caspase- and apoptosis inducing factor (AIF)-mediated apoptosis. These effects were associated with altered levels of proteins involved in cell cycle regulation, mitochondrial function, protein synthesis, endoplasmic reticulum stress, and metabolism; disruption of mortalin complexes with mitochondrial and metabolism proteins; and inhibition of oxidative phosphorylation and glycolysis. SHetA2 and paclitaxel exhibited synergistic combination indices in all cell lines and exerted greater xenograft tumor growth inhibition than either drug alone. SHetA2 is active against endometrial cancer cell lines in culture and in vivo and acts synergistically with paclitaxel.

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Mokbel, Kefah, Neill Patani, Wen Jiang, and Robert Newbold. "Prognostic implications of carboxyl-terminus of Hsc70 interacting protein and lysyl-oxidase expression in human breast cancer." Journal of Carcinogenesis 9, no. 1 (2010): 9. http://dx.doi.org/10.4103/1477-3163.72505.

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Kurozumi, Sasagu, Yuri Yamaguchi, Shin‐ichi Hayashi, Hiromi Hiyoshi, Tetsuji Suda, Tatsuyuki Gohno, Hiroshi Matsumoto, et al. "Prognostic value of the ubiquitin ligase carboxyl terminus of the Hsc70‐interacting protein in postmenopausal breast cancer." Cancer Medicine 5, no. 8 (June 23, 2016): 1873–82. http://dx.doi.org/10.1002/cam4.780.

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Li, Likun, Guang Yang, Chengzhen Ren, Ryuta Tanimoto, Takahiro Hirayama, Jianxiang Wang, David Hawke, et al. "Glioma pathogenesis-related protein 1 induces prostate cancer cell death through Hsc70-mediated suppression of AURKA and TPX2." Molecular Oncology 7, no. 3 (December 31, 2012): 484–96. http://dx.doi.org/10.1016/j.molonc.2012.12.005.

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Pellegrini, Paola, Karthik Selvaraju, Elena Faustini, Arjan Mofers, Xiaonan Zhang, Jens Ternerot, Alice Schubert, Stig Linder, and Pádraig D′Arcy. "Induction of ER Stress in Acute Lymphoblastic Leukemia Cells by the Deubiquitinase Inhibitor VLX1570." International Journal of Molecular Sciences 21, no. 13 (July 4, 2020): 4757. http://dx.doi.org/10.3390/ijms21134757.

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The proteasome is a validated target of cancer therapeutics. Inhibition of proteasome activity results in the activation of the unfolded protein response (UPR) characterized by phosphorylation of eukaryotic initiation factor 2α (eIF2α), global translational arrest, and increased expression of the proapoptotic CHOP (C/EBP homologous protein) protein. Defects in the UPR response has been reported to result in altered sensitivity of tumor cells to proteasome inhibitors. Here, we characterized the effects of the deubiquitinase (DUB) inhibitor VLX1570 on protein homeostasis, both at the level of the UPR and on protein translation, in acute lymphoblastic leukemia (ALL). Similar to the 20S inhibitor bortezomib, VLX1570 induced accumulation of polyubiquitinated proteins and increased expression of the chaperone Grp78/Bip in ALL cells. Both compounds induced cleavage of PARP (Poly (ADP-ribose) polymerase) in ALL cells, consistent with induction of apoptosis. However, and in contrast to bortezomib, VLX1570 treatment resulted in limited induction of the proapoptotic CHOP protein. Translational inhibition was observed by both bortezomib and VLX1570. We report that in distinction to bortezomib, suppression of translation by VXL1570 occurred at the level of elongation. Increased levels of Hsc70/Hsp70 proteins were observed on polysomes following exposure to VLX1570, possibly suggesting defects in nascent protein folding. Our findings demonstrate apoptosis induction in ALL cells that appears to be uncoupled from CHOP induction, and show that VLX1570 suppresses protein translation by a mechanism distinct from that of bortezomib.

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Lyupina, Yulia V., Olga V. Orlova, Svetlana B. Abaturova, Svetlana N. Beljelarskaya, Andrey N. Lavrov, and Victor S. Mikhailov. "Egress of budded virions of Autographa californica nucleopolyhedrovirus does not require activity of Spodoptera frugiperda HSP/HSC70 chaperones." Virus Research 192 (November 2014): 1–5. http://dx.doi.org/10.1016/j.virusres.2014.08.002.

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WANG, HANGHUI, YIXIN SONG, DINGJUN HAO, MIN BAI, LIFANG JIN, JIYING GU, YIJIN SU, LONG LIU, CHAO JIA, and LIANFANG DU. "Ultrasound-targeted microbubble destruction combined with dual targeting of HSP72 and HSC70 inhibits HSP90 function and induces extensive tumor-specific apoptosis." International Journal of Oncology 45, no. 1 (April 14, 2014): 157–64. http://dx.doi.org/10.3892/ijo.2014.2388.

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Sharma, Krishan K., Juan Felipe Rico, Duane C. Hassane, Gabriela Chiosis, and Monica L. Guzman. "Dysregulated Expression of HSP70 Isoforms in Acute Myelogenous Leukemia (AML)." Blood 118, no. 21 (November 18, 2011): 1370. http://dx.doi.org/10.1182/blood.v118.21.1370.1370.

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Abstract Abstract 1370 Stress-inducible heat shock protein 70 (HSP70) is a major cytoprotective factor and a molecular chaperone that interacts with HSP90 to form a multi-chaperone complex. Cancer cells are highly dependent on this complex due to their increased demand for protein synthesis. HSP70 overexpression inhibits apoptosis and has been associated with drug resistance. However, the contribution to drug resistance in AML of specific HSP70 isoforms remains unknown. As there is growing interest in therapeutically targeting HSP70, we investigated the expression of 7 different HSP70 isoforms in AML primary cells and leukemia cell lines and their response to a novel HSP70-inhbitor, YK5. A panel of 12 leukemia cell lines and 11 primary samples was used to determine the expression of HSP70 and their response to YK5. We also evaluated the changes to the HSP70 isoforms when exposed to either heat shock or YK5. We found MV4-11, MOLM-13, and U937 sensitive to YK5 (LD50 = 1.18μM, 1.03μM, and 2.31μM at 24 hours, respectively). In contrast, OCI-AML3, TUR and THP-1 were more resistant to the inhibitor. (LD50 = 9.92μM, 9.74μM, and 8.84μM at 24 hours, respectively). Non-tumor cells, however, were significantly less affected by treatment with YK5 (72% viable cord blood mononuclear cells after 24 hour treatment with 5μM YK5). We found that the cell surface expression of HSP70 was higher in both cell lines and primary samples when compared their normal counterparts. Furthermore, quantitative PCR revealed that cell lines with higher levels of HSPA1A and lower levels of HSPA6 demonstrated higher sensitivity to YK5. Interestingly, higher levels of HSPA1A and lower levels of HSPA6 were also found in primary AML samples when compared to CD34+ cord blood cells, consistent with the relative insensitivity of normal cells to YK5. We further discovered, mining publicly available databases, that high levels of HSPA1A were associated poorer prognosis (p = 0.004), suggesting that YK5 would be beneficial to patients presenting high HSP70 expression. We also evaluated the effect of YK5 on the gene expression of the various HSP70 isoforms. Quantitative PCR revealed the ability of YK5 to downregulate HSPA6 and HSC70 (HSPA8) in both cell lines and primary samples. Strikingly, all HSP70 isoforms exhibited similar fold changes upon heat shock in primary samples, CD34+ cord blood cells, and leukemia cell lines, indicating that the cellular stress response is not damaged in AML. However, the specificity of HSP70 inhibition to leukemia cells and not normal cells suggests a dysregulated set of client proteins and increased dependency on HSP70 to maintain leukemic homeostasis. In summary, we have found dysregulated expression of the HSP70 isoforms HSPA1A and HSPA6 in leukemia cells and that the expression levels of these isoforms correlate to the sensitivity of YK5-mediated HSP70 inhibition (HSPA1A: p=0.0012 and r2=0.801, HSPA6: p=0.0011 and r2=0.847). *KKS and JFR contributed equally to this project Disclosures: No relevant conflicts of interest to declare.

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Townsend, P. A., E. Dublin, I. R. Hart, R. H. Kao, A. M. Hanby, R. I. Cutress, R. Poulsom, K. Ryder, D. M. Barnes, and G. Packham. "BAG-1 expression in human breast cancer: interrelationship between BAG-1 RNA, protein, HSC70 expression and clinico-pathological data." Journal of Pathology 197, no. 1 (2002): 51–59. http://dx.doi.org/10.1002/path.1081.

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Mizukami, Shusaku, Chiaki Kajiwara, Hiroshi Ishikawa, Ichiro Katayama, Katsuyuki Yui, and Heiichiro Udono. "Both CD4+and CD8+T cell epitopes fused to heat shock cognate protein 70 (hsc70) can function to eradicate tumors." Cancer Science 99, no. 5 (May 2008): 1008–15. http://dx.doi.org/10.1111/j.1349-7006.2008.00788.x.

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Liu, Weiya, George A. Vielhauer, Jeffrey M. Holzbeierlein, Huiping Zhao, Suman Ghosh, Douglas Brown, Eugene Lee, and Brian S. J. Blagg. "KU675, a Concomitant Heat-Shock Protein Inhibitor of Hsp90 and Hsc70 that Manifests Isoform Selectivity for Hsp90α in Prostate Cancer Cells." Molecular Pharmacology 88, no. 1 (May 4, 2015): 121–30. http://dx.doi.org/10.1124/mol.114.097303.

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Guerrero, Rafael, Carlos Guerrero, and Orlando Acosta. "Induction of Cell Death in the Human Acute Lymphoblastic Leukemia Cell Line Reh by Infection with Rotavirus Isolate Wt1-5." Biomedicines 8, no. 8 (July 24, 2020): 242. http://dx.doi.org/10.3390/biomedicines8080242.

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Cancer is a major health problem that poses a great challenge to health care systems worldwide. Tools for cancer treatment have rapidly advanced in recent years, resulting in therapeutic strategies which are alternative and complementary to conventional treatment. To identify the cell surface receptors used by a tumor cell-adapted rotavirus and the cell death markers induced by its infection, we use Wt1-5, a rotavirus isolate recently adapted to tumor cells, to infect the human acute lymphoblastic leukemia cell line, Reh. The expression of cell surface receptors used by Wt1-5 was determined using flow cytometry and an antibody blocking assay to test for their implication in virus infection. Viral antigens and cell death markers induced by rotavirus infection were followed by flow cytometric analysis. The present study showed that rotavirus Wt1-5 was able to use cell surface proteins such as heat shock proteins (HSPs) 90, 70, 60 and 40, Hsc70, PDI and integrin β3. Rotavirus Wt1-5 induced cytotoxic effects including changes in cell membrane permeability, alteration of mitochondrial membrane potential, DNA fragmentation and activation of cell death signaling. Wt1-5 deserves to be further studied as a candidate oncolytic agent due to its ability to induce apoptosis in lymphoblastic leukemia-derived cells.

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Sharp, Adam, Ramsey I. Cutress, Peter W. M. Johnson, Graham Packham, and Paul A. Townsend. "Short peptides derived from the BAG-1 C-terminus inhibit the interaction between BAG-1 and HSC70 and decrease breast cancer cell growth." FEBS Letters 583, no. 21 (October 1, 2009): 3405–11. http://dx.doi.org/10.1016/j.febslet.2009.09.047.

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Alekseenko, Larisa, Mariia Shilina, Irina Kozhukharova, Olga Lyublinskaya, Irina Fridlyanskaya, Nikolay Nikolsky, and Tatiana Grinchuk. "Impact of Polyallylamine Hydrochloride on Gene Expression and Karyotypic Stability of Multidrug Resistant Transformed Cells." Cells 9, no. 10 (October 21, 2020): 2332. http://dx.doi.org/10.3390/cells9102332.

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The synthetic polymer, polyallylamine hydrochloride (PAA), is found in a variety of applications in biotechnology and medicine. It is used in gene and siRNA transfer, to form microcapsules for targeted drug delivery to damaged and tumor cells. Conventional chemotherapy often does not kill all cancer cells and leads to multidrug resistance (MDR). Until recently, studies of the effects of PAA on cells have mainly focused on their morphological and genetic characteristics immediately or several hours after exposure to the polymer. The properties of the cell progeny which survived the sublethal effects of PAA and resumed their proliferation, were not monitored. The present study demonstrated that treatment of immortalized Chinese hamster cells CHLV-79 RJK sensitive (RJK) and resistant (RJKEB) to ethidium bromide (EB) with cytotoxic doses of PAA, selected cells with increased karyotypic instability, were accompanied by changes in the expression of p53 genes c-fos, topo2-α, hsp90, hsc70. These changes did not contribute to the progression of MDR, accompanied by the increased sensitivity of these cells to the toxic effects of doxorubicin (DOX). Our results showed that PAA does not increase the oncogenic potential of immortalized cells and confirmed that it can be used for intracellular drug delivery for anticancer therapy.

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Lyu, Tae Seong, Yoojin Ahn, Young-Jun Im, Seong-Soo Kim, Ki-Heon Lee, Jinyoung Kim, Yujin Choi, et al. "The characterization of exosomes from fibrosarcoma cell and the useful usage of Dynamic Light Scattering (DLS) for their evaluation." PLOS ONE 16, no. 1 (January 26, 2021): e0231994. http://dx.doi.org/10.1371/journal.pone.0231994.

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Exosomes are a type of extracellular vesicles containing mRNA, miRNA, and proteins of origin cells, which can control the characteristics of other cells or surroundings. Despite increasing evidence on oncogenic properties of tumor-derived exosomes, fibrosarcoma-derived exosomes remain largely unrevealed. While the proper extraction and characterization of exosomes is critical in exosomes research, there are various limitations in techniques to measure the size and homogeneity of exosomes. Here, we analyzed exosomes from a fibrosarcoma cell line WEHI-164 compared with a breast cancer cell line MDA-MD-231 as a control. Results from dot blot and western blot analysis demonstrated that GM1 ganglioside, and TSG101, HSC70 and GAPDH proteins were contained in exosomes from the WEHI-164 fibrosarcoma cell line. The existence of tetraspanins such as CD81, CD63 and CD9 was confirmed in the exosomes by ExoView analysis. The results obtained from TEM showed their sphere-like shapes of around 50 to 70 nm in radius. Through DLS, we found out that the mean radius of the exosomes derived from WEHI-164 and MDA-MB-231 cell lines was 94.4 nm and 107.8 nm, respectively, with high homogeneity. When comparing the radius measured by TEM with the radius measured by DLS, it was revealed that the difference between the two methods was about 40 nm. This study has significance in characterizing the molecular properties of exosomes from a fibrosarcoma, which has not been researched much before, and in providing clear evidence that DLS can be used as an efficient, convenient and noninvasive technique to simply check the homogeneity and size of exosomes.

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Wu, H. Helena, Benfan Wang, Stephen R. Armstrong, Yasser Abuetabh, Sarah Leng, Wilson H. Y. Roa, Azeddine Atfi, et al. "Hsp70 acts as a fine-switch that controls E3 ligase CHIP-mediated TAp63 and ΔNp63 ubiquitination and degradation." Nucleic Acids Research 49, no. 5 (February 22, 2021): 2740–58. http://dx.doi.org/10.1093/nar/gkab081.

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Abstract The major clinical problem in human cancer is metastasis. Metastases are the cause of 90% of human cancer deaths. TAp63 is a critical suppressor of tumorigenesis and metastasis. ΔNp63 acts as a dominant-negative inhibitor to block the function of p53 and TAp63. Although several ubiquitin E3 ligases have been reported to regulate p63 stability, the mechanism of p63 regulation remains partially understood. Herein, we show that CHIP, an E3 ligase with a U-box domain, physically interacts with p63 and promotes p63 degradation. Notably, Hsp70 depletion by siRNA stabilizes TAp63 in H1299 cells and destabilizes ΔNp63 in SCC9 cells. Loss of Hsp70 results in a reduction in the TAp63-CHIP interaction in H1299 cells and an increase in the interaction between ΔNp63 and CHIP in SCC9 cells. Our results reveal that Hsp70 acts as a molecular switch to control CHIP-mediated ubiquitination and degradation of p63 isoforms. Furthermore, regulation of p63 by the Hsp70-CHIP axis contributes to the migration and invasion of tumor cells. Hence, our findings demonstrate that Hsp70 is a crucial regulator of CHIP-mediated ubiquitination and degradation of p63 isoforms and identify a new pathway for maintaining TAp63 or ΔNp63 stability in cancers.

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Albakova, Zarema, Grigoriy A. Armeev, Leonid M. Kanevskiy, Elena I. Kovalenko, and Alexander M. Sapozhnikov. "HSP70 Multi-Functionality in Cancer." Cells 9, no. 3 (March 2, 2020): 587. http://dx.doi.org/10.3390/cells9030587.

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The 70-kDa heat shock proteins (HSP70s) are abundantly present in cancer, providing malignant cells selective advantage by suppressing multiple apoptotic pathways, regulating necrosis, bypassing cellular senescence program, interfering with tumor immunity, promoting angiogenesis and supporting metastasis. This direct involvement of HSP70 in most of the cancer hallmarks explains the phenomenon of cancer “addiction” to HSP70, tightly linking tumor survival and growth to the HSP70 expression. HSP70 operates in different states through its catalytic cycle, suggesting that it can multi-function in malignant cells in any of these states. Clinically, tumor cells intensively release HSP70 in extracellular microenvironment, resulting in diverse outcomes for patient survival. Given its clinical significance, small molecule inhibitors were developed to target different sites of the HSP70 machinery. Furthermore, several HSP70-based immunotherapy approaches were assessed in clinical trials. This review will explore different roles of HSP70 on cancer progression and emphasize the importance of understanding the flexibility of HSP70 nature for future development of anti-cancer therapies.

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Chakafana, Graham, and Addmore Shonhai. "The Role of Non-Canonical Hsp70s (Hsp110/Grp170) in Cancer." Cells 10, no. 2 (January 28, 2021): 254. http://dx.doi.org/10.3390/cells10020254.

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Although cancers account for over 16% of all global deaths annually, at present, no reliable therapies exist for most types of the disease. As protein folding facilitators, heat shock proteins (Hsps) play an important role in cancer development. Not surprisingly, Hsps are among leading anticancer drug targets. Generally, Hsp70s are divided into two main subtypes: canonical Hsp70 (Escherichia coli Hsp70/DnaK homologues) and the non-canonical (Hsp110 and Grp170) members. These two main Hsp70 groups are delineated from each other by distinct structural and functional specifications. Non-canonical Hsp70s are considered as holdase chaperones, while canonical Hsp70s are refoldases. This unique characteristic feature is mirrored by the distinct structural features of these two groups of chaperones. Hsp110/Grp170 members are larger as they possess an extended acidic insertion in their substrate binding domains. While the role of canonical Hsp70s in cancer has received a fair share of attention, the roles of non-canonical Hsp70s in cancer development has received less attention in comparison. In the current review, we discuss the structure-function features of non-canonical Hsp70s members and how these features impact their role in cancer development. We further mapped out their interactome and discussed the prospects of targeting these proteins in cancer therapy.

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He, Lei, Tao Deng, and He-sheng Luo. "Heat Shock Protein 70 Gene Polymorphisms and Cancer Risk: A Meta-Analysis." Scientific World Journal 2014 (2014): 1–9. http://dx.doi.org/10.1155/2014/540309.

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The polymorphisms in the three main heat shock protein 70 (HSP70-1, HSP70-2, and HSP70-hom) genes were identified to be associated with cancer risk. However, the results are inconsistent. We perform a meta-analysis to evaluate the association between the three HSP70 polymorphisms and cancer risk. Relevant studies were identified using PubMed, Web of Science, Chinese National Knowledge Infrastructure (CNKI), and Wanfang databases up to March 29, 2014. The cancer risk associated with the HSP70 polymorphisms was estimated for each study by odds ratios (OR) together with its 95% confidence interval (CI), respectively. Twenty case-control studies from eighteen publications were included; a significant association was observed for HSP70-2 polymorphism (dominant model: OR = 1.53, 95% CI: 1.11–2.09; recessive model: OR = 1.91, 95% CI: 1.06–3.45; AG versus AA: OR = 1.38, 95% CI: 1.03–1.84; GG versus AA: OR = 2.34, 95% CI: 1.21–4.54), while there was no significant association for HSP70-1 and HSP70-hom polymorphisms. Besides, in stratification analyses by ethnicity, cancer type, and source of control, significant association was detected for HSP70-2 polymorphism, while for HSP70-hom polymorphism, we found a significant association in hospital-based population under homozygote comparison model. This meta-analysis suggests that the HSP70-2 polymorphism rather than HSP70-hom and HSP70-1 polymorphisms was associated with the risk of cancer.

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Soleimani, Atena, Elnaz Zahiri, Sajad Ehtiati, Mahtab Norouzi, Farzad Rahmani, Hamid Fiuji, Amir Avan, et al. "Therapeutic potency of heat-shock protein-70 in the pathogenesis of colorectal cancer: current status and perspectives." Biochemistry and Cell Biology 97, no. 2 (April 2019): 85–90. http://dx.doi.org/10.1139/bcb-2018-0177.

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Heat-shock protein-70 (HSP70) is critical to the folding, stability, and activity of several client proteins including many responsible for cancer cell proliferation, apoptosis, drug toxicity, and metastasis. Up-regulation of HSP70 is positively associated with increased tumorigenicity as well as poor survival in colon cancer patients, supporting the diagnostic, prognostic, and therapeutic potencies of HSP70 in colorectal cancer. The administration of specific pharmacological inhibitors or gene knock-down for HSP70 suppresses tumor progression and enhances tumor cell chemosensitivity. This review summarizes the different tumorigenic properties of HSP70 and the potential therapeutic potency of HSP70 inhibitors in terms of a novel strategy for colorectal cancer therapy, for a better understanding, and hence better management of this disease.

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Tang, Tielong, Chao Yang, Ham Ebo Brown, and Jing Huang. "Circulating Heat Shock Protein 70 Is a Novel Biomarker for Early Diagnosis of Lung Cancer." Disease Markers 2018 (August 29, 2018): 1–8. http://dx.doi.org/10.1155/2018/6184162.

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Heat shock protein 70 (HSP70) was a highly conserved protein which was significantly induced in response to cellular stresses. HSP70 played an important role in the pathogenesis of cancer which stabilized the production of large amount of oncogenic proteins and finally supported growth and survival of tumor. However, there was no report about the diagnosis of circulating HSP70 in lung cancer patients. In this study, a total of 297 participants (lung cancer: 197, healthy control: 100) were enrolled in the detection of circulating HSP70 level in plasma by ELISA assay. The results indicated that circulating HSP70 significantly decreased in lung cancer patients compared to healthy controls (P<0.0001). Receiver operating characteristic (ROC) analysis showed that HSP70 (AUC: 82.2%, SN: 74.1%, SP: 80.0%) had higher diagnosis value than clinical existing biomarkers CEA (AUC: 80.1%, SN: 76.8%, SP: 67.3%) and CA 19-9 (AUC: 63.7%, SN: 64.2%, SP: 54.0%). In the analysis of early lung cancer patients, ROC results also revealed that HSP70 (AUC: 83.8%, SN: 71.2%, SP: 84.0%) have higher sensitivity, specificity, and AUC than CEA (AUC: 73.7%, SN: 73.2%, SP: 69.1%) and CA 19-9 (AUC: 61.5%, SN: 69.4%, SP: 53.4%). In analysis of specific histological classifications, HSP70 showed more valuable in the diagnosis of SCC (AUC: 85.9%, SN: 86.1.9%, SP: 81.0%) than ADC (AUC: 81.0%, SN: 69.1%, SP: 81.0%). Combined analysis of HSP70 and existing biomarker: CEA and CA 19-9 exhibited that HSP70 combined CEA and CA 19-9 showed the highest AUC (0.945, 95% CI, 0.855–1.000). The importance of our results was that we found decreased circulating HSP70, in combination with elevated CEA and CA 19-9, could be utilized in the diagnosis of early (stage I and II) lung cancer.

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Komarova, Elena Y., Larisa V. Marchenko, Alexander V. Zhakhov, Alina D. Nikotina, Nikolay D. Aksenov, Roman V. Suezov, Alexander M. Ischenko, Boris A. Margulis, and Irina V. Guzhova. "Extracellular Hsp70 Reduces the Pro-Tumor Capacity of Monocytes/Macrophages Co-Cultivated with Cancer Cells." International Journal of Molecular Sciences 21, no. 1 (December 20, 2019): 59. http://dx.doi.org/10.3390/ijms21010059.

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Cancer cells are known to contain high levels of the heat shock protein 70 kDa (Hsp70), which mediates increased cell proliferation, escape from programmed cell death, enhanced invasion, and metastasis. A part of Hsp70 molecules may release from cancer cells and affect the behavior of adjacent stromal cells. To explore the effects of Hsp70 on the status of monocytes/macrophages in the tumor locale, we incubated human carcinoma cells of three distinct lines with normal and reduced content of Hsp70 with THP1 monocytes. Using two methods, we showed that the cells with knock-down of Hsp70 released a lower amount of protein in the extracellular medium. Three cycles of the co-cultivation of cancer and monocytic cells led to the secretion of several cytokines typical of the tumor microenvironment (TME) and to pro-cancer activation of the monocytes/macrophages as established by elevation of F4/80 and arginase-1 markers. Unexpectedly, the efficacy of epithelial–mesenchymal transition and resistance of carcinoma cells to anticancer drugs after incubation with monocytic cells were more pronounced in cells with lower Hsp70, e.g., releasing less Hsp70 into the extracellular milieu. These data suggest that Hsp70 released from tumor cells into the TME is able, together with the development of an anti-cancer immune response, to limit the conversion of a considerable part of monocytic cells to the pro-tumor phenotype.

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Gao, Shanshan, Ning Pu, Hanlin Yin, Junhao Li, Qiangda Chen, Minjie Yang, Wenhui Lou, et al. "Radiofrequency ablation in combination with an mTOR inhibitor restrains pancreatic cancer growth induced by intrinsic HSP70." Therapeutic Advances in Medical Oncology 12 (January 2020): 175883592095372. http://dx.doi.org/10.1177/1758835920953728.

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Background: Radiofrequency ablation (RFA) is widely used in palliative therapy of malignant cancers. Several studies have shown its applicability and safety for locally advanced pancreatic cancer (LAPC). The objective of this study was to modify the current regimen to improve its therapeutic effect. Methods: Immune cell subtypes and related cytokines were quantified to uncover the immune pattern changes post-RFA treatment. Then, high-throughput proteome analysis was performed to identify differentially expressed proteins associated with RFA, which were further validated in in vitro and in vivo experiments. Finally, a combined therapy was tested in a murine model to observe its therapeutic effect. Results: In preclinical murine models of RFA treatment, no significant therapeutic benefit was observed following RFA treatment. However, the proportion of tumor-infiltrating CD8+ T cells was significantly increased, whereas that of regulatory T cells (Tregs) was decreased post-RFA treatment, which indicated a beneficial anti-tumor environment. To identify the mechanism, high-throughput mass spectrum was obtained that identified heat shock protein 70 (HSP70) as the top differentially expressed protein. HSP70 expression in residual cancer cells was significantly increased post-RFA treatment, which notably promoted pancreatic cancer growth. Elevated HSP70 promoted cell proliferation by activating AKT–mTOR signaling. Finally, RFA treatment combined with an mTOR inhibitor exerted a synergetic repressive effect on tumor growth in the preclinical murine cancer model. Conclusions: RFA treatment in combination with mTOR signaling blockade can not only promote tumor immune response, but also restrain residual cancer cell proliferation. Such a combination may be a promising and effective therapeutic strategy for LAPC patients.

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Dmytryk, V., Y. Zinkova, and O. Savchuk. "Contents of HSP60 and HSP70 in tumor tissues of patients with bladder cancer." Bulletin of Taras Shevchenko National University of Kyiv. Series: Biology 77, no. 1 (2019): 79–82. http://dx.doi.org/10.17721/1728_2748.2019.77.79-82.

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Bladder cancer (BC) continues to be a disease with a high mortality rate. BC is the 9th most frequently diagnosed cancer in the world. According to statistics, the largest number of patients with BC patients in developed countries. About 75 % of patients are men. Various molecules have been identified as potential prognostic indicators and/or targets for a given disease. However, the search for targets for the treatment and prevention of BC remains relevant. Recently, studies have been conducted on the participation of heat shock proteins (HSPs) in malignant neoplasms. In which high expression of HSPs is associated with the protection of transformed cells and the blocking of apoptosis. Data on overexpression of HSPs have been published for a number of oncological diseases, including breast, cervical, colon, lung and prostate cancers. Recent studies have closely linked the level of HSPs expression with the subsequent prognosis of the disease. The aim of the work was to identify the dynamics of HSP70 and HSP60 in tumors and walls of a healthy bladder in BC patients, depending on the stage of cancer with the TNM classification, and also on the degree of cell differentiation. In our study, an increase in HSPs content in homogenates of tumors was found in comparison with samples of healthy bladder walls, that is, an increase in HSPs content may be associated with BC. An increase in the content HSP60 and HSP70 was noted, depending on the BC stage, as well as on the degree of cell differentiation. A high level of HSP expression can ensure the correct folding and membrane transport of products of oncogenes and anti-oncogenes. On the other hand, high synthesis of HSPs can regulate the process of protein degradation and quickly normalize protein metabolism in cancer cells, ensuring the rapid growth of malignant tumors.

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Gao, Guangyu, Songtao Liu, Zhen Yao, Yanyan Zhan, Wenyue Chen, and Yulong Liu. "The Prognostic Significance of Hsp70 in Patients with Colorectal Cancer Patients: A PRISMA-Compliant Meta-Analysis." BioMed Research International 2021 (April 16, 2021): 1–7. http://dx.doi.org/10.1155/2021/5526327.

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Background. Hsp70 (heat shock protein 70) plays a key role in carcinogenesis and cancer progression. However, the relationship between the Hsp70 expression level and the colorectal cancer patient survival is unknown. This study is aimed at investigating the relationship between Hsp70 and the prognosis of colorectal carcinoma patients. Methods. PubMed, Web of Science, and Embase were used for systematic computer literature retrieval. Stata SE14.0 software was used for quantitative meta-analysis. Besides, data was extracted from selected articles. Relationships between Hsp70 expression level and prognosis were further studied. The hazard ratios (HRs) and 95% confidence intervals (95% CIs) were also computed. Results. A total of 11 potentially eligible studies with 2269 patients were identified in 10 tumors from PubMed, Web of Science, and Embase. Hsp70 overexpression was associated with poor overall survival (OS) and disease-free survival (DFS) in colorectal carcinoma patients (HRs, 0.65 (95% CI: 0.52-0.78) and 0.77 (95% CI: 0.23-1.32), respectively). Conclusions. Hsp70 overexpression can predict poor survival in colorectal cancer patients.

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Calderwood, Stuart K. "Molecular Cochaperones: Tumor Growth and Cancer Treatment." Scientifica 2013 (2013): 1–13. http://dx.doi.org/10.1155/2013/217513.

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Molecular chaperones play important roles in all cellular organisms by maintaining the proteome in an optimally folded state. They appear to be at a premium in cancer cells whose evolution along the malignant pathways requires the fostering of cohorts of mutant proteins that are employed to overcome tumor suppressive regulation. To function at significant rates in cells, HSPs interact with cochaperones, proteins that assist in catalyzing individual steps in molecular chaperoning as well as in posttranslational modification and intracellular localization. We review current knowledge regarding the roles of chaperones such as heat shock protein 90 (Hsp90) and Hsp70 and their cochaperones in cancer. Cochaperones are potential targets for cancer therapy in themselves and can be used to assess the likely prognosis of individual malignancies. Hsp70 cochaperones Bag1, Bag3, and Hop play significant roles in the etiology of some cancers as do Hsp90 cochaperones Aha1, p23, Cdc37, and FKBP1. Others such as the J domain protein family, HspBP1, TTC4, and FKBPL appear to be associated with more benign tumor phenotypes. The key importance of cochaperones for many pathways of protein folding in cancer suggests high promise for the future development of novel pharmaceutical agents.

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Wang, Hao, Meng-Shan Tan, Rui-Chun Lu, Jin-Tai Yu, and Lan Tan. "Heat Shock Proteins at the Crossroads between Cancer and Alzheimer’s Disease." BioMed Research International 2014 (2014): 1–9. http://dx.doi.org/10.1155/2014/239164.

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Heat shock proteins 70 and heat shock proteins 90 (Hsp70/90) have been implicated in many crucial steps of carcinogenesis: stabilizing oncogenic proteins, inhibiting programmed cell death and replicative senescence, induction of tumor angiogenesis, and activation of the invasion and metastasis. Plenty of cancer related proteins have the ability of regulating the expression of Hsp70/90 through heat shock factor 1. Cancer and Alzheimer’s disease (AD) have plenty of overlapping regions in molecular genetics and cell biology associated with Hsp70/90. The Hsp70, as a protein stabilizer, has a cellular protection against neurodegeneration of the central nervous system, while Hsp90 promote neurodegenerative disorders indirectly through regulating the expression of Hsp70 and other chaperones. All these make existing anticancer drugs target Hsp70/90 which might be used in AD therapy.

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Chang, Chih-Shiang, Vathan Kumar, Der-Yen Lee, Yeh Chen, Yu-Chieh Wu, Jing-Yan Gao, and Po-Chen Chu. "Development of Novel Rhodacyanine-Based Heat Shock Protein 70 Inhibitors." Current Medicinal Chemistry 28, no. 26 (September 8, 2021): 5431–46. http://dx.doi.org/10.2174/0929867328666210203204254.

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Background: A growing body of evidence suggests that Hsp70, which is overexpressed in human breast tumors, plays a role in tumorigenesis and tumor progression in breast cancer as well as in its aggressive phenotypes. Hsp70 constitutes a potential therapeutic target in the treatment of this disease. Methods: We developed a new series of rhodacyanine-based Hsp70 inhibitors, represented by compounds 1 and 6, in which the cationic pyridin-1-ium or thiazol-3-ium ring of existing Hsp70 inhibitors (e.g., JG-40 and JG-98) was replaced by a corresponding benzo- fused N-heterocycle. Results: Several lines of evidence suggest that these benzo-fused derivatives may exert their antitumor activities, in part, by targeting Hsp70. These putative inhibitors displayed differential antiproliferative efficacy against breast cancer cells (IC50 as low as 0.25 μM) versus nontumorigenic MCF-10A breast epithelial cells (IC50 ≥ 5 μM). This was correlated with the corresponding Hsp70 expression levels. Using a protein refolding assay, we confirmed that these agents effectively inhibited the chaperone activity of Hsp70. Moreover, these inhibitors effectively suppressed the expression of well-known oncogenic client proteins of Hsp70’s, including FoxM1, HuR, and Akt, which paralleled their antiproliferative efficacy. Supporting the established role of Hsp70 in regulating protein refolding, these derivatives induced autophagy, as manifested by the conversion of LC3B-I to LC3B-II. Notably, these putative Hsp70 inhibitors did not cause a compensatory elevation in Hsp90 expression, contrasting with the previously reported effects of Hsp90 inhibitors on Hsp70 upregulation. Conclusion: Together with the finding that compounds 1 and 6 showed improved microsomal stability, these results suggest the translational potential of these putative Hsp70 inhibitors to foster new strategies for cancer therapy. However, whether these benzo-fused rhodacyanines act on kinases or other targets remains unclear. It is currently under investigation.

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Söderström, Henna, Juha Kauppi, Jari Räsänen, and Tuomo Rantanen. "PS02.043: OVEREXPRESSION OF HSP27 AND HSP70 ARE ASSOCIATED WITH DECREASED SURVIVAL AMONG PATIENTS WITH ESOPHAGEAL ADENOCARCINOMA." Diseases of the Esophagus 31, Supplement_1 (September 1, 2018): 132. http://dx.doi.org/10.1093/dote/doy089.ps02.043.

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Abstract Background Heat shock protein (HSP) 27 and 70 overexpression is associated with several malignancies but reports of their incidence and association with survival among patients with esophageal carcinoma (EC) are scarce. COX-2 expression is induced by inflammation, and it has been linked to a Barrett's esophagus and a wide variety of cancers. High COX-2 expression has been linked to poor survival in EC but results regarding association to clinicopathological factors are conflicting. Methods Immunohistochemical analysis for HSP27, HSP70 and COX-2 was performed on 97 cancer cases, 19 Barrett cases and 5 controls treated between 1990 - 2007. Data was gathered from patient records and survival data was acquired in December 2015. Results Higher tumor stage was significantly associated with poorer survival (P < 0001), which was independent of HSP27, HSP70 and COX-2 immunostaining. HSP27 was moderately or strongly positive in 61,8% of the cancer cases, which was significantly associated to poorer survival (25,6 and 19 months versus 65,1 in weakly positive samples) (P = 0,01). Similar results were seen for HSP70, for which 30,4% of the cases were stained moderately or strong positive, and survival was 15 and 17,3 months compared to 41,7 months in weakly stained cases. COX-2 was negative in 83,3% of the cancer cases, and none of the samples had strong COX-2 immunostaining. COX-2 did not correlate with survival. Conclusion Moderate or high HSP27 and HSP70 staining intensities were associated with poor survival among patients with esophageal adenocarcinoma, which is now reported for the first time. According to previous studies opposite conclusions for esophageal squamous cell carcinoma was found. COX-2 did not impact survival in our study even though it's been found to be a negative prognostic factor in several previous studies. Disclosure All authors have declared no conflicts of interest.

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Pigłowski, Wojciech, Radosława Nowak, Zdzisław Krawczyk, and Dorota Scieglińska. "The structural and functional analysis of the human HSPA2 gene promoter region." Acta Biochimica Polonica 54, no. 1 (March 20, 2007): 99–106. http://dx.doi.org/10.18388/abp.2007_3274.

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HSPA2 is a human counterpart of the testis-specific rodent Hst70/Hsp70.2 gene. In contrast to the latter, the expression of the human HSPA2 gene is not limited to the testis, and recent data show that human tumor cells can express this gene at significant levels. The characteristics of HSPA2 expression suggests that it can influence the phenotype and survival of cancer cells similarly as overexpression of major members of the HSP70 gene family. Until now, neither the structure of the transcription unit of the human HSPA2 gene has been established nor a functional analysis of its promoter performed. In this study we established that the human HSPA2 gene, in contrast to its rodent counterparts, is intronless and has a single transcription start site. We also show that the same type of HSPA2 transcripts are synthesized in the testes and in cancer cell lines. In order to perform a functional study of the HSPA2 promoter, we used a transient transfection assay and found that the 392 bp fragment upstream of the ATG codon was a minimal region required for efficient transcription, while a 150 bp deletion from the 5' end of this region dramatically reduced the promoter activity. Delineation of the minimal promoter is a basic step toward identifying the cis and trans elements involved in the regulation of the HSPA2 gene expression in cancer cells.

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Journal articles on the topic 'HSC70; Cancer'

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