Current Science

Open Access Open Access  Restricted Access Subscription Access

The Role of TRAP1, the Mitochondrial Hsp90 in Cancer Progression and as a Possible Therapeutic Target


Affiliations
1 Department of Zoology, Gurudas College, 1/1 Suren Sarkar Road, Narkeldanga, Kolkata 700 054, India
 

Hsp90, a 90 kDa heat shock protein (HSP), is a molecular chaperone involved in various cellular processes. It is highly conserved across species and plays a critical role in protein folding quality control, protein degradation and, most importantly, stabilizing proteins against heat stress. Emerging evidences suggest that HSPs accumulate not only in stressful conditions, but also in patho-physiological conditions and tumours. They play a role in refolding partially damaged functional proteins and also stabilize cell survival factors. Studies also suggest the role of organelle-specific Hsp90 chaperones in these processes, which further adds to the complexity. These findings make the Hsp90 family a potent target for anti-cancer drugs. Tumour necrosis factor receptor-associated protein 1 (TRAP1), the mitochondrial homolog of Hsp90, is found to play a pivotal role in mitochondrial bioenergetics, maintenance of mitochondrial integrity and mounting stress responses. Tumour cells exhibit a peculiar phenotype known as the Warburg effect, where they evade the mitochondrial oxidative phosphorylation and produce ATP by aerobic glycolysis. Studies suggest TRAP1 as a key regulator in this metabolic switchover along with a pivotal role in drug resistance and anti-apoptotic effects. This article discusses the molecular mechanisms of TRAP1 to regulate cancer growth, its role in protecting cells from apoptosis and toxicity from anti-cancer drugs. The possibility of TRAP1 as a potential target for cancer therapies in the near future based on new-age therapeutic strategies by inhibiting the protein is also discussed here.

Keywords

Apoptosis, Cancer Progression, Drug Resistance, Heat Shock Proteins, Tumour Cells.
User
Notifications
Font Size

  • Lindquist, S., The heat-shock response. Annu. Rev. Biochem., 1986, 55, 1151–1191.

  • Ritossa, F., A new puffing pattern induced by temperature shock and DNP in Drosophila. Experientia, 1962, 18(12), 571–573.

  • Hoter, A., El-Sabban, M. E. and Naim, H. Y., The HSP90 family: structure, regulation, function, and implications in health and disease. Int. J. Mol. Sci., 2018, 19(9), 2560.

  • Pirkkala, L. and Sistonen, L., Heat shock proteins (HSPs): structure, function and genetics. Encycl. Life Sci., 2006, 1–7.

  • Macario, A. J. and Conway de Macario, E., Molecular chaperones: multiple functions, pathologies, and potential applications. Front. Biosci., 2007, 12, 2588–2600.

  • Wu, J., Liu, T., Rios, Z., Mei, Q., Lin, X. and Cao, S., Heat shock proteins and cancer. Trends Pharmacol. Sci., 2017, 38(3), 226–256.

  • Kampinga, H. H. et al., Guidelines for the nomenclature of the human heat shock proteins. Cell Stress Chaperones, 2009, 14(1), 105–111.

  • Csermely, P., Schnaider, T., Soti, C., Prohászka, Z. and Nardai, G., The 90-kDa molecular chaperone family: structure, function, and clinical applications. A comprehensive review. Pharmacol. Ther., 1998, 79(2), 129–168.

  • Pearl, L. H., Structure, function, and mechanism of the Hsp90 molecular chaperone. Adv. Protein Chem., 2001, 59, 157–186.

  • Grammatikakis, N. et al., The role of Hsp90N, a new member of the Hsp90 family, in signal transduction and neoplastic transformation. J. Biol. Chem., 2007, 277(10), 8312–8320.

  • Sreedhar, A. S., Kalmár, E., Csermely, P. and Shen, Y. F., Hsp90 isoforms functions, expression and clinical importance. FEBS Lett., 2004, 562(1–3), 11–15.

  • Song, H. Y., Dunbar, J. D., Zhang, Y. X., Guo, D. and Donner, D. B., Identification of a protein with homology to hsp90 that binds the type 1 tumor necrosis factor receptor. J. Biol. Chem., 1995, 270(8), 3574–3581.

  • Felts, S. J., Owen, B. A., Nguyen, P., Trepel, J., Donner, D. B. and Toft, D. O., The Hsp90-related protein TRAP1 is a mitochondrial protein with distinct functional properties. J. Biol. Chem., 2000, 275(5), 3305–3312.

  • Cechetto, J. D. and Gupta, R. S., Immunoelectron microscopy provides evidence that tumor necrosis factor receptor-associated protein 1 (TRAP-1) is a mitochondrial protein which also localizes at specific extramitochondrial sites. Exp. Cell Res., 2000, 260(1), 30–39.

  • Amoroso, M. R., Matassa, D. S., Sisinni, L., Lettini, G., Landriscina, M. and Esposito, F., TRAP1 revisited: novel localizations and functions of a ‘next-generation’ biomarker (review). Int. J. Oncol., 2014, 45(3), 969–977.

  • Im, C. N., Past, present, and emerging roles of mitochondrial heat shock protein TRAP1 in the metabolism and regulation of cancer stem cells. Cell Stress Chaperones, 2016, 21(4), 553–562.

  • Li, X. T., Li, Y. S., Shi, Z. Y. and Guo, X. L., New insights into molecular chaperone TRAP1 as a feasible target for future cancer treatments. Life Sci., 2020, 254, 117737.

  • Lettini, G. et al., TRAP1: a viable therapeutic target for future cancer treatments? Expert Opin. Ther. Targets, 2017, 21(8), 805–815.

  • Butler, L. M., Ferraldeschi, R., Armstrong, H. K., Centenera, M. M. and Workman, P., Maximizing the therapeutic potential of HSP90 inhibitors. Mol. Cancer Res., 2015, 13(11), 1445–1451.

  • Le Bras, G. et al., New novobiocin analogues as antiproliferative agents in breast cancer cells and potential inhibitors of heat shock protein 90. J. Med. Chem., 2007, 50(24), 6189–6200.

  • Radanyi, C. et al., Antiproliferative and apoptotic activities of tosylcyclonovobiocic acids as potent heat shock protein 90 inhibitors in human cancer cells. Cancer Lett., 2009, 274(1), 88–94.

  • Samadi, A. K., Zhang, X., Mukerji, R., Donnelly, A. C., Blagg, B. S. and Cohen, M. S., A novel C-terminal HSP90 inhibitor KU135 induces apoptosis and cell cycle arrest in melanoma cells. Cancer Lett., 2011, 312(2), 158–167.

  • Altieri, D. C., Stein, G. S., Lian, J. B. and Languino, L. R., TRAP-1, the mitochondrial Hsp90. Biochim. Biophys. Acta, 2012, 1823(3), 767–773.

  • Sung, N., Lee, J., Kim, J. H., Chang, C., Tsai, F. T. and Lee, S., 2.4 Å resolution crystal structure of human TRAP1NM, the Hsp90 paralog in the mitochondrial matrix. Acta Crystallogr. Sect. D., 2016, 72(Pt8), 904–911.

  • Lavery, L. A., Partridge, J. R., Ramelot, T. A., Elnatan, D., Kennedy, M. A. and Agard, D. A., Structural asymmetry in the closed state of mitochondrial Hsp90 (TRAP1) supports a two-step ATP hydrolysis mechanism. Mol. Cell, 2014, 53(2), 330–343.

  • Partridge, J. R., Lavery, L. A., Elnatan, D., Naber, N., Cooke, R. and Agard, D. A., A novel N-terminal extension in mitochondrial TRAP1 serves as a thermal regulator of chaperone activity. Elife, 2014, 3, e03487.

  • Cunningham, C. N., Southworth, D. R., Krukenberg, K. A. and Agard, D. A., The conserved arginine 380 of Hsp90 is not a catalytic residue, but stabilizes the closed conformation required for ATP hydrolysis. Protein Sci., 2012, 21(8), 1162–1171.

  • Leskovar, A., Wegele, H., Werbeck, N. D., Buchner, J. and Reinstein, J., The ATPase cycle of the mitochondrial Hsp90 analog Trap1. J. Biol. Chem., 2008, 283(17), 11677–11688.

  • Hinkle, P. C., P/O ratios of mitochondrial oxidative phosphorylation. Biochim. Biophys. Acta, 2005, 1706(1–2), 1–11.

  • DeBerardinis, R. J., Lum, J. J., Hatzivassiliou, G. and Thompson, C. B., The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metlab., 2008, 7(1), 11–20.

  • Lu, J., Tan, M. and Cai, Q., The Warburg effect in tumor progression: mitochondrial oxidative metabolism as an anti-metastasis mechanism. Cancer Lett., 2015, 356(2 Pt A), 156–164.

  • Koppenol, W. H., Bounds, P. L. and Dang, C. V., Otto Warburg’s contributions to current concepts of cancer metabolism. Nature Rev. Cancer, 2011, 11(5), 325–337.

  • Lebelo, M. T., Joubert, A. M. and Visagie, M. H., Warburg effect and its role in tumourigenesis. Arch. Pharm. Res., 2019, 42(10), 833–847.

  • Warburg, O., Wind, F. and Negelein, E., The metabolism of tumors in the body. J. Gen. Physiol., 1927, 8(6), 519–530.

  • Weinhouse, S., Warburg, O., Burk, D. and Schade, A. L., On respiratory impairment in cancer cells. Science, 1956, 124(3215), 270–272.

  • Fais, S., Venturi, G. and Gatenby, B., Microenvironmental acidosis in carcinogenesis and metastases: new strategies in prevention and therapy. Cancer Metastasis Rev., 2014, 33(4), 1095–1108.

  • Viale, A., Corti, D. and Draetta, G. F., Tumors and mitochondrial respiration: a neglected connection. Cancer Res., 2015, 75(18), 3685–3686.

  • Mayers, J. R. et al., Tissue of origin dictates branched-chain amino acid metabolism in mutant Kras-driven cancers. Science, 2016, 353(6304), 1161–1165.

  • Avolio, R., Matassa, D. S., Criscuolo, D., Landriscina, M. and Esposito, F., Modulation of mitochondrial metabolic reprogramming and oxidative stress to overcome chemoresistance in cancer. Biomolecules, 2020, 10(1), 135.

  • Xie, S., Wang, X., Gan, S., Tang, X., Kang, X. and Zhu, S., The mitochondrial chaperone TRAP1 as a candidate target of oncotherapy. Front. Oncol., 2021, 10,

  • Matassa, D. S., Agliarulo, I., Avolio, R., Landriscina, M. and Esposito, F., TRAP1 regulation of cancer metabolism: dual role as oncogene or tumor suppressor. Genes (Basel), 2018, 9(4), 195.

  • Sciacovelli, M. et al., The mitochondrial chaperone TRAP1 promotes neoplastic growth by inhibiting succinate dehydrogenase. Cell Metlab., 2013, 17(6), 988–999.

  • Yoshida, S. et al., Molecular chaperone TRAP1 regulates a metabolic switch between mitochondrial respiration and aerobic glycolysis. Proc. Natl. Acad. Sci. USA, 2013, 110(17), E1604–E1612.

  • Ramkumar, B., Dharaskar, S. P., Mounika, G., Paithankar, K. and Sreedhar, A. S., Mitochondrial chaperone, TRAP1 as a potential pharmacological target to combat cancer metabolism. Mitochondrion, 2020, 50, 42–50.

  • Cluntun, A. A., Lukey, M. J., Cerione, R. A. and Locasale, J. W., Glutamine metabolism in cancer: understanding the heterogeneity. Trends Cancer, 2017, 3(3), 169–180.

  • Joshi, A. et al., The mitochondrial HSP90 paralog TRAP1 forms an OXPHOS-regulated tetramer and is involved in mitochondrial metabolic homeostasis. BMC Biol., 2020, 18(1), 10.

  • Agliarulo, I. et al., TRAP1 controls cell migration of cancer cells in metabolic stress conditions: correlations with AKT/p70S6K pathways. Biochim. Biophys. Acta, 2015, 1853(10 Pt A), 2570– 2579.

  • Vo, V. T. A. et al., TRAP1 inhibition increases glutamine synthetase activity in glutamine auxotrophic Non-Small Cell Lung Cancer Cells. Anticancer Res., 2018, 38(4), 2187–2193.

  • Yoon, N. G. et al., Mitoquinone inactivates mitochondrial chaperone TRAP1 by blocking the client binding site. J. Am. Chem. Soc., 2021, 143(47), 19684–19696.

  • Gordan, J. D. and Simon, M. C., Hypoxia-inducible factors: central regulators of the tumor phenotype. Curr. Opin. Genet. Dev., 2007, 17(1), 71–77.

  • Denko, N. C., Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nature Rev. Cancer, 2008, 8(9), 705–713.

  • Selak, M. A. et al., Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell, 2005, 7(1), 77–85.

  • Jenkins, C. M., Yang, J., Sims, H. F. and Gross, R. W., Reversible high affinity inhibition of phosphofructokinase-1 by acyl-CoA: a mechanism integrating glycolytic flux with lipid metabolism. J. Biol. Chem., 2011, 286(14), 11937–11950.

  • Kemp, R. G. and Gunasekera, D., Evolution of the allosteric ligand sites of mammalian phosphofructo-1-kinase. Biochemistry, 2002, 41(30), 9426–9430.

  • Maddalena, F. et al., TRAP1 enhances Warburg metabolism through modulation of PFK1 expression/activity and favors resistance to EGFR inhibitors in human colorectal carcinomas. Mol. Oncol., 2020, 14(12), 3030–3047.

  • Lee, H. and Yoon, Y., Mitochondrial fission and fusion. Biochem. Soc. Trans., 2016, 44(6), 1725–1735.

  • Youle, R. J. and van der Bliek, A. M., Mitochondrial fission, fusion, and stress. Science, 2012, 337(6098), 1062–1065.

  • Anderson, G. R. et al., Dysregulation of mitochondrial dynamics proteins are a targetable feature of human tumors. Nature Commun., 2018, 9(1), 1677.

  • Han, Y., Cho, U., Kim, S., Park, I. S., Cho, J. H., Dhanasekaran, D. N. and Song, Y. S., Tumour microenvironment on mitochondrial dynamics and chemoresistance in cancer. Free Radic. Res., 2018, 52(11–12), 1271–1287.

  • Takamura, H. et al., TRAP1 controls mitochondrial fusion/fission balance through Drp1 and Mff expression. PLoS ONE, 2012, 7(12), e51912.

  • Purushottam Dharaskar, S., Paithankar, K., Kanugovi Vijayavittal, A., Shabbir Kara, H. and Amere Subbarao, S., Mitochondrial chaperone, TRAP1 modulates mitochondrial dynamics and promotes tumor metastasis. Mitochondrion, 2020, 54, 90–101.

  • Zhang, B. et al., Aberrantly upregulated TRAP1 is required for tumorigenesis of breast cancer. Oncotarget, 2015, 6(42), 44495– 44508.

  • Turrens, J. F., Mitochondrial formation of reactive oxygen species. J. Physiol., 2003, 552(Pt 2), 335–344.

  • Guzzo, G., Sciacovelli, M., Bernardi, P. and Rasola, A., Inhibition of succinate dehydrogenase by the mitochondrial chaperone TRAP1 has anti-oxidant and anti-apoptotic effects on tumor cells. Oncotarget, 2014, 5(23), 11897–11908.

  • Im, C. N., Lee, J. S., Zheng, Y. and Seo, J. S., Iron chelation study in a normal human hepatocyte cell line suggests that tumor necrosis factor receptor-associated protein 1 (TRAP1) regulates production of reactive oxygen species. J. Cell. Biochem., 2007, 100(2), 474– 486.

  • Montesano Gesualdi, N., Chirico, G., Pirozzi, G., Costantino, E., Landriscina, M. and Esposito, F., Tumor necrosis factor-associated protein 1 (TRAP-1) protects cells from oxidative stress and apoptosis. Stress, 2007, 10(4), 342–350.

  • Hua, G., Zhang, Q. and Fan, Z., Heat shock protein 75 (TRAP1) antagonizes reactive oxygen species generation and protects cells from granzyme M-mediated apoptosis. J. Biol. Chem., 2007, 282(28), 20553–20560.

  • Li, P. et al., Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell, 1997, 91(4), 479–489.

  • Lu, H., Hou, Q., Zhao, T., Zhang, H., Zhang, Q., Wu, L. and Fan, Z., Granzyme M directly cleaves inhibitor of caspase-activated DNase (CAD) to unleash CAD leading to DNA fragmentation. J. Immunol., 2006, 177(2), 1171–1178.

  • Baines, C. P. et al., Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature, 2005, 434(7033), 658–662.

  • Kang, B. H., Plescia, J., Dohi, T., Rosa, J., Doxsey, S. J. and Altieri, D. C., Regulation of tumor cell mitochondrial homeostasis by an organelle-specific Hsp90 chaperone network. Cell, 2007, 131(2), 257–270.

  • Lebedev, I. et al., A novel in vitro CypD-mediated p53 aggregation assay suggests a model for mitochondrial permeability transition by chaperone systems. J. Mol. Biol., 2016, 428(20), 4154–4167.

  • Kim, J. S., Wang, J. H. and Lemasters, J. J., Mitochondrial permeability transition in rat hepatocytes after anoxia/reoxygenation: role of Ca2+-dependent mitochondrial formation of reactive oxygen species. Am. J. Physiol. Gastrointest. Liver Physiol., 2011, 302(7), G723–G731.

  • Bonora, M., Bravo-San Pedro, J. M., Kroemer, G., Galluzzi, L. and Pinton, P., Novel insights into the mitochondrial permeability transition. Cell Cycle, 2014, 13(17), 2666–2670.

  • Zhang, B., Jia, K., Tian, J. and Du, H., Cyclophilin D counterbalances mitochondrial calcium uniporter-mediated brain mitochondrial calcium uptake. Biochem. Biophys. Res. Commun., 2020, 529(2), 314–320.

  • Xiang, F., Huang, Y. S., Shi, X. H. and Zhang, Q., Mitochondrial chaperone tumour necrosis factor receptor-associated protein 1 protects cardiomyocytes from hypoxic injury by regulating mitochondrial permeability transition pore opening. FEBS J., 2010, 277(8), 1929–1938.

  • Liu, L., Zhang, L., Zhao, J., Guo, X., Luo, Y., Hu, W. and Zhao, T., Tumor necrosis factor receptor-associated protein 1 protects against mitochondrial injury by preventing high glucose-induced mPTP opening in diabetes. Oxid. Med. Cell Longev., 2020, 2020, 6431517.

  • Masuda, Y. et al., Involvement of tumor necrosis factor receptorassociated protein 1 (TRAP1) in apoptosis induced by beta-hydroxyisovalerylshikonin. J. Biol. Chem., 2004, 279(41), 42503–42515.

  • Tian, X. et al., Suppression of tumor necrosis factor receptor-associated protein 1 expression induces inhibition of cell proliferation and tumor growth in human esophageal cancer cells. FEBS J., 2014, 281(12), 2805–2819.

  • Agorreta, J. et al., TRAP1 regulates proliferation, mitochondrial function, and has prognostic significance in NSCLC. Mol. Cancer Res., 2014, 12(5), 660–669.

  • Ariës, I. M. et al., PRC2 loss induces chemoresistance by repressing apoptosis in T cell acute lymphoblastic leukemia. J. Exp. Med., 2018, 215(12), 3094–3114.

  • Ron, D. and Walter, P., Signal integration in the endoplasmic reticulum unfolded protein response. Nature Rev. Mol. Cell Biol., 2007, 8(7), 519–529.

  • Hetz, C., The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nature Rev. Mol. Cell Biol., 2012, 13(2), 89–102.

  • Takemoto, K., Miyata, S., Takamura, H., Katayama, T. and Tohyama, M., Mitochondrial TRAP1 regulates the unfolded protein response in the endoplasmic reticulum. Neurochem. Int., 2011, 58(8), 880–887.

  • Amoroso, M. R. et al., TRAP1 and the proteasome regulatory particle TBP7/Rpt3 interact in the endoplasmic reticulum and control cellular ubiquitination of specific mitochondrial proteins. Cell Death Differ., 2012, 19(4), 592–604.

  • Matassa, D. S. et al., Translational control in the stress adaptive response of cancer cells: a novel role for the heat shock protein TRAP1. Cell Death Dis., 2013, 4(10), e851.

  • Costantino, E. et al., TRAP1, a novel mitochondrial chaperone responsible for multi-drug resistance and protection from apoptosis in human colorectal carcinoma cells. Cancer Lett., 2009, 279(1), 39– 46.

  • Landriscina, M. et al., Mitochondrial chaperone TRAP1 and the calcium binding protein sorcin interact and protect cells against apoptosis induced by antiblastic agents. Cancer Res., 2010, 70(16), 6577–6586.

  • Maddalena, F. et al., Resistance to paclitxel in breast carcinoma cells requires a quality control of mitochondrial antiapoptotic proteins by TRAP1. Mol. Oncol., 2013, 7(5), 895–906.

  • Zhang, X. et al., Knockdown of TRAP1 promotes cisplatininduced apoptosis by promoting the ROS-dependent mitochondrial dysfunction in lung cancer cells. Mol. Cell Biochem., 2021, 476(2), 1075–1082.

  • Sisinni, L., Maddalena, F., Lettini, G., Condelli, V., Matassa, D. S., Esposito, F. and Landriscina, M., TRAP1 role in endoplasmic reticulum stress protection favors resistance to anthracyclins in breast carcinoma cells. Int. J. Oncol., 2014, 44(2), 573–582.

  • Palladino, G. et al., TRAP1 regulates cell cycle and apoptosis in thyroid carcinoma cells. Endocr. Relat. Cancer, 2016, 23(9), 699–709.

  • Matassa, D. S. et al., Oxidative metabolism drives inflammationinduced platinum resistance in human ovarian cancer. Cell Death Differ., 2016, 23(9), 1542–1554.

  • Liu, D. et al., Tumor necrosis factor receptor-associated protein 1(TRAP1) regulates genes involved in cell cycle and metastases. Cancer Lett., 2010, 296(2), 194–205.

  • Chen, C. F., Chen, Y., Dai, K., Chen, P. L., Riley, D. J. and Lee, W. H., A new member of the hsp90 family of molecular chaperones interacts with the retinoblastoma protein during mitosis and after heat shock. Mol. Cell Biol., 1996, 16(9), 4691–4699.

  • Hu, J. et al., TRAP1 is involved in cell cycle regulated by retinoblastoma susceptibility gene (RB1) in early hypoxia and has variable expression patterns in human tumors. J. Cancer Res. Updates, 2013, 2, 194–210.

  • Coller, H. A., Grandori, C., Tamayo, P., Colbert, T., Lander, E. S. and Golub, T. R., Expression analysis with oligonucleotide microarrays reveals that MYC regulates genes involved in growth, cell cycle, signaling, and adhesion. Proc. Natl. Acad. Sci. USA, 2000, 97(7), 3260–3265.

  • Dang, C. V., MYC on the path to cancer. Cell, 2012, 149(1), 22–35.

  • Agarwal, E. et al., Myc-mediated transcriptional regulation of the mitochondrial chaperone TRAP1 controls primary and metastatic tumor growth. J. Biol. Chem., 2019, 294(27), 10407–10414.

  • Sisinni, L. et al., TRAP1 controls cell cycle G2-M transition through the regulation of CDK1 and MAD2 expression/ ubiquitination. J. Pathol., 2017, 243(1), 123–134.

  • Pak, M. G., Koh, H. J. and Roh, M. S., Clinicopathologic significance of TRAP1 expression in colorectal cancer: a large scale study of human colorectal adenocarcinoma tissues. Diagn. Pathol., 2017, 12(1), 6.

  • Gao, J. Y., Song, B. R., Peng, J. J. and Lu, Y. M., Correlation between mitochondrial TRAP-1 expression and lymph node metastasis in colorectal cancer. World J. Gastroenterol., 2012, 18(41), 5965– 5971.

  • Gao, C. et al., Overexpression of the mitochondrial chaperone tumor necrosis factor receptor-associated protein 1 is associated with the poor prognosis of patients with colorectal cancer. Oncol. Lett., 2018, 15(4), 5451–5458.

  • Leav, I. et al., Cytoprotective mitochondrial chaperone TRAP-1 as a novel molecular target in localized and metastatic prostate cancer. Am. J. Pathol., 2010, 176(1), 393–401.

  • Han, P., Wang, Q. L. and Zhang, X., Expression of TRAP1 in gastric cancer tissue and its correlation with malignant biology. Asian Pac. J. Trop. Med., 2016, 9(1), 67–71.

  • Si, T., Yang, G., Qiu, X., Luo, Y., Liu, B. and Wang, B., Expression of tumor necrosis factor receptor-associated protein 1 and its clinical significance in kidney cancer. Int. J. Clin. Exp. Pathol., 2015, 8(10), 13090–13095.

  • Lv, Q., Sun, H., Cao, C., Gao, B. and Qi, Y., Overexpression of tumor necrosis factor receptor-associated protein 1 (TRAP1) is associated with poor prognosis of epithelial ovarian cancer. Tumour Biol., 2016, 37(2), 2721–2727.

  • Maddalena, F. et al., TRAP1 protein signature predicts outcome in human metastatic colorectal carcinoma. Oncotarget, 2017, 8(13), 21229–21240.

  • Amoroso, M. R. et al., TRAP1 downregulation in human ovarian cancer enhances invasion and epithelial–mesenchymal transition. Cell Death Dis., 2016, 7(12), e2522.

  • Wu, J., Liu, Y., Cho, K., Dong, X., Teng, L. and Han, D., Downregulation of TRAP1 sensitizes glioblastoma cells to temozolomide chemotherapy through regulating metabolic reprogramming. Neuroreport, 2016, 27(3), 136–144.

  • Lisanti, S. et al., Transgenic expression of the mitochondrial chaperone TNFR-associated Protein 1 (TRAP1) accelerates prostate cancer development. J. Biol. Chem., 2016, 291(48), 25247–25254.

  • Ou, Y. et al., TRAP1 shows clinical significance and promotes cellular migration and invasion through STAT3/MMP2 pathway in human esophageal squamous cell cancer. J. Genet. Genomics, 2014, 41(10), 529–537.

  • Yadav, L., Puri, N., Rastogi, V., Satpute, P., Ahmad, R. and Kaur, G., Matrix metalloproteinases and cancer – roles in threat and therapy. Asian Pac. J. Cancer Prev., 2014, 15(3), 1085–1091.

  • Nissinen, L. and Kähäri, V. M., Matrix metalloproteinases in inflammation. Biochim. Biophys. Acta, 2004, 1840(8), 2571–2580.

  • Zhou, Y., Li, G., Wu, J., Zhang, Z. and Wu, Z., Clinicopathological significance of E-cadherin, VEGF, and MMPs in gastric cancer. Tumour Biol., 2010, 31(6), 549–558.

  • Jun, K. H. et al., Clinicopathological significance of N-cadherin and VEGF in advanced gastric cancer brain metastasis and the effects of metformin in preclinical models. Oncol. Rep., 2015, 34(4), 2047–2053.

  • Testa, J. R. and Bellacosa, A., AKT plays a central role in tumorigenesis. Proc. Natl. Acad. Sci. USA, 2001, 98(20), 10983–10985.

  • Berven, L. A., Willard, F. S. and Crouch, M. F., Role of the p70(S6K) pathway in regulating the actin cytoskeleton and cell migration. Exp. Cell Res., 2004, 296(2), 183–195.

  • Matassa, D. S. et al., TRAP1-dependent regulation of p70S6K is involved in the attenuation of protein synthesis and cell migration: relevance in human colorectal tumors. Mol. Oncol., 2014, 8(8), 1482–-1494.

  • Yin, H. et al., Down-regulation of STIP1 regulate apoptosis and invasion of glioma cells via TRAP1/AKT signaling pathway. Cancer Genet., 2019, 237, 1–9.

  • Condelli, V. et al., TRAP1 is involved in BRAF regulation and downstream attenuation of ERK phosphorylation and cell-cycle progression: a novel target for BRAF-mutated colorectal tumors. Cancer Res., 2014, 74(22), 6693–6704.

  • Condelli, V. et al., Targeting TRAP1 as a downstream effector of BRAF cytoprotective pathway: a novel strategy for human BRAFdriven colorectal carcinoma. Oncotarget, 2015, 6(26), 22298–22309.

  • Liang, H. L., He, X. Y., Yang, W. X., Wang, L. and Yang, Y., Expression of TRAP1 and BRAF(V600E) gene mutation in papillary thyroid cancer and its correlation analysis (in Chinese). Shandong Med. J., 2018, 58(11), 22–25.

  • Im, C. N. and Seo, J. S., Overexpression of tumor necrosis factor receptor-associated protein 1 (TRAP1), leads to mitochondrial aberrations in mouse fibroblast NIH/3T3 cells. BMB Rep., 2014, 47(5), 280–285.

  • Masgras, I. et al., Absence of neurofibromin induces an oncogenic metabolic switch via mitochondrial ERK-mediated phosphorylation of the chaperone TRAP1. Cell Rep., 2017, 18(3), 659–672.

  • Caino, M. C. et al., Metabolic stress regulates cytoskeletal dynamics and metastasis of cancer cells. J. Clin. Invest, 2013, 123(7), 2907– 2920.

  • Chae, Y. C. et al., Control of tumor bioenergetics and survival stress signaling by mitochondrial HSP90s. Cancer Cell, 2012, 22(3), 331–344.

  • Kabakov, A., Yakimova, A. and Matchuk, O., Molecular chaperones in cancer stem cells: determinants of stemness and potential targets for antitumor therapy. Cells, 2020, 9(4), 892.

  • Lettini, G. et al., TRAP1 regulates stemness through Wnt/β-catenin pathway in human colorectal carcinoma. Cell Death Differ., 2016, 23(11), 1792–1803.

  • Park, H. K. et al., Interplay between TRAP1 and sirtuin-3 modulates mitochondrial respiration and oxidative stress to maintain stemness of glioma stem cells. Cancer Res., 2019, 79(7), 1369–1382.

  • Wang, Y. et al., Overexpression of mitochondrial Hsp75 protects neural stem cells against microglia-derived soluble factor-induced neurotoxicity by regulating mitochondrial permeability transition pore opening in vitro. Int. J. Mol. Med., 2015, 36(6), 1487–1496.

  • Altieri, D. C., Validating survivin as a cancer therapeutic target. Nature Rev. Cancer, 2003, 3(1), 46–54.

  • Fortugno, P., Beltrami, E., Plescia, J., Fontana, J. and Pradhan, D., Regulation of survivin function by Hsp90. Proc. Natl. Acad. Sci. USA, 2003, 100(24), 13791–13796.

  • Plescia, J. et al., Rational design of shepherdin, a novel anticancer agent. Cancer Cell, 2005, 7(5), 457–468.

  • Siegelin, M. D., Inhibition of the mitochondrial Hsp90 chaperone network: a novel, efficient treatment strategy for cancer? Cancer Lett., 2013, 333(2), 133–146.

  • Siegelin, M. D., Plescia, J., Raskett, C. M., Gilbert, C. A., Ross, A. H. and Altieri, D. C., Global targeting of subcellular heat shock protein-90 networks for therapy of glioblastoma. Mol. Cancer Ther., 2010, 9(6), 1638–1646.

  • Venkatesan, N., Kanwar, J. R., Deepa, P. R., Navaneethakrishnan, S., Joseph, C. and Krishnakumar, S., Targeting Hsp90/survivin using a cell permeable structure based peptido-mimetic shepherdin in retinoblastoma. Chem. Biol. Interact., 2016, 252, 141–149.

  • Kang, B. H. et al., Combinatorial drug design targeting multiple cancer signaling networks controlled by mitochondrial Hsp90. J. Clin. Invest., 2009, 119(3), 454–464.

  • Chakafana, G. and Shonhai, A., The role of non-canonical Hsp70s (Hsp110/Grp170) in cancer. Cells, 2021, 10(2), 254.

  • Siegelin, M. D. et al., Exploiting the mitochondrial unfolded protein response for cancer therapy in mice and human cells. J. Clin. Invest., 2011, 121(4), 1349–1360.

  • Kang, B. H. et al., Targeted inhibition of mitochondrial Hsp90 suppresses localised and metastatic prostate cancer growth in a genetic mouse model of disease. Br. J. Cancer, 2011, 104(4), 629–634.

  • Lee, C. et al., Development of a mitochondria-targeted Hsp90 inhibitor based on the crystal structures of human TRAP1. J. Am. Chem. Soc., 2015, 137(13), 4358–4367.

  • Park, H. K. et al., Paralog specificity determines subcellular distribution, action mechanism, and anticancer activity of TRAP1 inhibitors. J. Med. Chem., 2017, 60(17), 7569–7578.

  • Menezes, D. L. et al., The novel oral Hsp90 inhibitor NVP-HSP990 exhibits potent and broad-spectrum antitumor activities in vitro and in vivo. Mol. Cancer Ther., 2012, 11(3), 730–739.

  • Zhang, L., Pang, E., Loo, R. R., Rao, J., Go, V. L., Loo, J. A. and Lu, Q. Y., Concomitant inhibition of HSP90, its mitochondrial localized homologue TRAP1 and HSP27 by green tea in pancreatic cancer HPAF-II cells. Proteomics, 2011, 11(24), 4638–4647.

  • Sanchez-Martin, C. et al., Honokiol bis-dichloroacetate is a selective allosteric inhibitor of the mitochondrial chaperone TRAP1. Antioxid. Redox Signal., 2021, 34(7), 505–516.

  • Park, H. K. et al., Combination treatment with doxorubicin and gamitrinib synergistically augments anticancer activity through enhanced activation of Bim. BMC Cancer, 2014, 14, 1431.

  • Nguyen, T. T. T. et al., Inhibition of HDAC1/2 along with TRAP1 causes synthetic lethality in glioblastoma model systems. Cells, 2020, 9(7), 1661.

  • Nguyen, T. T. T. et al., Activation of LXR receptors and inhibition of TRAP1 causes synthetic lethality in solid tumors. Cancers (Basel), 2019, 11(6), 788.

  • Amash, V., Paithankar, K., Purushottam Dharaskar, S., Arunachalam, A. and Amere Subbarao, S., Development of nanocarrier-based mitochondrial chaperone, TRAP-1 inhibitor to combat cancer metabolism. ACS Appl. Bio Mater., 2020, 3(7), 4188–4197.

  • D’Annessa, I. et al., Design of allosteric stimulators of the Hsp90 ATPase as new anticancer leads. Chemistry, 2017, 23(22), 5188–5192.

  • Sanchez-Martin, C. et al., Rational design of allosteric and selective inhibitors of the molecular chaperone TRAP1. Cell Rep., 2020, 31(3), 107531.

  • Yu, L. et al., Modeling the genetic regulation of cancer metabolism: interplay between glycolysis and oxidative phosphorylation. Cancer Res., 2017, 77(7), 1564–1574.

  • Jeon, S. M. and Hay, N., The double-edged sword of AMPK signaling in cancer and its therapeutic implications. Arch. Pharm. Res., 2015, 8(3), 346–357.


Abstract Views: 242

PDF Views: 142




  • The Role of TRAP1, the Mitochondrial Hsp90 in Cancer Progression and as a Possible Therapeutic Target

Abstract Views: 242  |  PDF Views: 142

Authors

Sena Sarkar
Department of Zoology, Gurudas College, 1/1 Suren Sarkar Road, Narkeldanga, Kolkata 700 054, India
Babli Halder
Department of Zoology, Gurudas College, 1/1 Suren Sarkar Road, Narkeldanga, Kolkata 700 054, India

Abstract


Hsp90, a 90 kDa heat shock protein (HSP), is a molecular chaperone involved in various cellular processes. It is highly conserved across species and plays a critical role in protein folding quality control, protein degradation and, most importantly, stabilizing proteins against heat stress. Emerging evidences suggest that HSPs accumulate not only in stressful conditions, but also in patho-physiological conditions and tumours. They play a role in refolding partially damaged functional proteins and also stabilize cell survival factors. Studies also suggest the role of organelle-specific Hsp90 chaperones in these processes, which further adds to the complexity. These findings make the Hsp90 family a potent target for anti-cancer drugs. Tumour necrosis factor receptor-associated protein 1 (TRAP1), the mitochondrial homolog of Hsp90, is found to play a pivotal role in mitochondrial bioenergetics, maintenance of mitochondrial integrity and mounting stress responses. Tumour cells exhibit a peculiar phenotype known as the Warburg effect, where they evade the mitochondrial oxidative phosphorylation and produce ATP by aerobic glycolysis. Studies suggest TRAP1 as a key regulator in this metabolic switchover along with a pivotal role in drug resistance and anti-apoptotic effects. This article discusses the molecular mechanisms of TRAP1 to regulate cancer growth, its role in protecting cells from apoptosis and toxicity from anti-cancer drugs. The possibility of TRAP1 as a potential target for cancer therapies in the near future based on new-age therapeutic strategies by inhibiting the protein is also discussed here.

Keywords


Apoptosis, Cancer Progression, Drug Resistance, Heat Shock Proteins, Tumour Cells.

References





DOI: https://doi.org/10.18520/cs%2Fv124%2Fi6%2F671-685