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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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TRAP1 regulation of mitochondrial life or death decision in cancer cells and mitochondria-targeted TRAP1 inhibitors

  • Kang, Byoung-Heon (Graduate Program of Life Science, School of Nano-Bioscience and Chemical Engineering, and C5 Science Research Center, UNIST)
  • Accepted : 2011.10.22
  • Published : 2012.01.31
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Abstract

Hsp90 is one of the most conserved molecular chaperones ubiquitously expressed in normal cells and over-expressed in cancer cells. A pool of Hsp90 was found in cancer mitochondria and the expression of the mitochondrial Hsp90 homolog, TRAP1, was also elevated in many cancers. The mitochondrial pool of chaperones plays important roles in regulating mitochondrial integrity, protecting against oxidative stress, and inhibiting cell death. Pharmacological inactivation of the chaperones induced mitochondrial dysfunction and concomitant cell death selectively in cancer cells, suggesting they can be target proteins for the development of cancer therapeutics. Several drug candidates targeting TRAP1 and Hsp90 in the mitochondria have been developed and have shown strong cytotoxic activity in many cancers, but not in normal cells in vitro and in vivo. In this review, recent developments in the study of mitochondrial chaperones and the mitochondria-targeted chaperone inhibitors are discussed.

Keywords

References

  1. Welch, W. J. (1991) The role of heat-shock proteins as molecular chaperones. Curr. Opin. Cell. Biol. 3, 1033-1038. https://doi.org/10.1016/0955-0674(91)90125-I
  2. Hightower, L. E. (1991) Heat shock, stress proteins, chaperones, and proteotoxicity. Cell 66, 191-197. https://doi.org/10.1016/0092-8674(91)90611-2
  3. Whitesell, L. and Lindquist, S. L. (2005) HSP90 and the chaperoning of cancer. Nat. Rev. Cancer 5, 761-772. https://doi.org/10.1038/nrc1716
  4. Pearl, L. H. and Prodromou, C. (2006) Structure and mechanism of the Hsp90 molecular chaperone machinery. Annu. Rev. Biochem. 75, 271-294. https://doi.org/10.1146/annurev.biochem.75.103004.142738
  5. Feder, M. E. and Hofmann, G. E. (1999) Heat-shock proteins, molecular chaperones, and the stress response: evolutionary and ecological physiology. Annu. Rev. Physiol. 61, 243-282. https://doi.org/10.1146/annurev.physiol.61.1.243
  6. Taipale, M., Jarosz, D. F. and Lindquist, S. (2010) HSP90 at the hub of protein homeostasis: emerging mechanistic insights. Nat. Rev. Mol. Cell. Biol. 11, 515-528. https://doi.org/10.1038/nrm2918
  7. Bagatell, R. and Whitesell, L. (2004) Altered Hsp90 function in cancer: a unique therapeutic opportunity. Mol. Cancer Ther. 3, 1021-1030. https://doi.org/10.4161/cbt.3.10.1142
  8. Blagg, B. S. and Kerr, T. D. (2006) Hsp90 inhibitors: small molecules that transform the Hsp90 protein folding machinery into a catalyst for protein degradation. Med. Res. Rev. 26, 310-338. https://doi.org/10.1002/med.20052
  9. Solit, D. B. and Chiosis, G. (2008) Development and application of Hsp90 inhibitors. Drug Discov. Today 13, 38-43. https://doi.org/10.1016/j.drudis.2007.10.007
  10. Biamonte, M. A., Van de Water, R., Arndt, J. W., Scannevin, R. H., Perret, D. and Lee, W. C. (2010) Heat shock protein 90: inhibitors in clinical trials. J. Med. Chem. 53, 3-17. https://doi.org/10.1021/jm9004708
  11. Chen, B., Piel, W. H., Gui, L., Bruford, E. and Monteiro, A. (2005) The HSP90 family of genes in the human genome: insights into their divergence and evolution. Genomics. 86, 627-637. https://doi.org/10.1016/j.ygeno.2005.08.012
  12. Song, H. Y., Dunbar, J. D., Zhang, Y. X., Guo, D. and Donner, D. B. (1995) Identification of a protein with homology to hsp90 that binds the type 1 tumor necrosis factor receptor. J. Biol. Chem. 270, 3574-3581. https://doi.org/10.1074/jbc.270.8.3574
  13. Chen, C. F., Chen, Y., Dai, K., Chen, P. L., Riley, D. J. and Lee, W. H. (1996) A new member of the hsp90 family of molecular chaperones interacts with the retinoblastoma protein during mitosis and after heat shock. Mol. Cell. Biol. 16, 4691-4699. https://doi.org/10.1128/MCB.16.9.4691
  14. Felts, S. J., Owen, B. A., Nguyen, P., Trepel, J., Donner, D. B. and Toft, D. O. (2000) The hsp90-related protein TRAP1 is a mitochondrial protein with distinct functional properties. J. Biol. Chem. 275, 3305-3312. https://doi.org/10.1074/jbc.275.5.3305
  15. Leskovar, A., Wegele, H., Werbeck, N. D., Buchner, J. and Reinstein, J. (2008) The ATPase cycle of the mitochondrial Hsp90 analog Trap1. J. Biol. Chem. 283, 11677-11688. https://doi.org/10.1074/jbc.M709516200
  16. Kang, B. H., Plescia, J., Dohi, T., Rosa, J., Doxsey, S. J. and Altieri, D. C. (2007) Regulation of tumor cell mitochondrial homeostasis by an organelle-specific Hsp90 chaperone network. Cell 131, 257-270. https://doi.org/10.1016/j.cell.2007.08.028
  17. Kang, B. H., Plescia, J., Song, H. Y., Meli, M., Colombo, G., Beebe, K., Scroggins, B., Neckers, L. and Altieri, D. C. (2009) Combinatorial drug design targeting multiple cancer signaling networks controlled by mitochondrial Hsp90. J. Clin. Invest. 119, 454-464. https://doi.org/10.1172/JCI37613
  18. Schleiff, E. and Becker, T. (2011) Common ground for protein translocation: access control for mitochondria and chloroplasts. Nat. Rev. Mol. Cell. Biol. 12, 48-59. https://doi.org/10.1038/nrm3027
  19. Simmons, A. D., Musy, M. M., Lopes, C. S., Hwang, L. Y., Yang, Y. P. and Lovett, M. (1999) A direct interaction between EXT proteins and glycosyltransferases is defective in hereditary multiple exostoses. Hum. Mol. Genet. 8, 2155-2164. https://doi.org/10.1093/hmg/8.12.2155
  20. Deocaris, C. C., Kaul, S. C. and Wadhwa, R. (2006) On the brotherhood of the mitochondrial chaperones mortalin and heat shock protein 60. Cell Stress Chaperones 11, 116-128. https://doi.org/10.1379/CSC-144R.1
  21. Patten, D. A., Germain, M., Kelly, M. A. and Slack, R. S. (2010) Reactive oxygen species: stuck in the middle of neurodegeneration. J. Alzheimers Dis. 20(Suppl 2), S357-367. https://doi.org/10.3233/JAD-2010-100498
  22. Sotgia, F., Martinez-Outschoorn, U. E. and Lisanti, M. P. (2011) Mitochondrial oxidative stress drives tumor progression and metastasis: should we use antioxidants as a key component of cancer treatment and prevention? BMC Med. 9, 62. https://doi.org/10.1186/1741-7015-9-62
  23. Masuda, Y., Shima, G., Aiuchi, T., Horie, M., Hori, K., Nakajo, S., Kajimoto, S., Shibayama-Imazu, T. and Nakaya, K. (2004) Involvement of tumor necrosis factor receptor- associated protein 1 (TRAP1) in apoptosis induced by beta-hydroxyisovalerylshikonin. J. Biol. Chem. 279, 42503-42515. https://doi.org/10.1074/jbc.M404256200
  24. Montesano Gesualdi, N., Chirico, G., Pirozzi, G., Costantino, E., Landriscina, M. and Esposito, F. (2007) Tumor necrosis factor-associated protein 1 (TRAP-1) protects cells from oxidative stress and apoptosis. Stress 10, 342-350. https://doi.org/10.1080/10253890701314863
  25. Hua, G., Zhang, Q. and Fan, Z. (2007) Heat shock protein 75 (TRAP1) antagonizes reactive oxygen species generation and protects cells from granzyme M-mediated apoptosis. J. Biol. Chem. 282, 20553-20560. https://doi.org/10.1074/jbc.M703196200
  26. Im, C. N., Lee, J. S., Zheng, Y. and Seo, J. S. (2007) 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. 100, 474-486. https://doi.org/10.1002/jcb.21064
  27. Siegelin, M. D., Dohi, T., Raskett, C. M., Orlowski, G. M., Powers, C. M., Gilbert, C. A., Ross, A. H., Plescia, J. and Altieri, D. C. (2011) Exploiting the mitochondrial unfolded protein response for cancer therapy in mice and human cells. J. Clin. Invest. 121, 1349-1360. https://doi.org/10.1172/JCI44855
  28. Mattson, M. P. and Kroemer, G. (2003) Mitochondria in cell death: novel targets for neuroprotection and cardioprotection. Trends Mol. Med. 9, 196-205. https://doi.org/10.1016/S1471-4914(03)00046-7
  29. Kroemer, G., Galluzzi, L. and Brenner, C. (2007) Mitochondrial membrane permeabilization in cell death. Physiol. Rev. 87, 99-163. https://doi.org/10.1152/physrev.00013.2006
  30. Tsujimoto, Y., Nakagawa, T. and Shimizu, S. (2006) Mitochondrial membrane permeability transition and cell death. Biochim. Biophys. Acta. 1757, 1297-1300. https://doi.org/10.1016/j.bbabio.2006.03.017
  31. Baines, C. P., Kaiser, R. A., Sheiko, T., Craigen, W. J. and Molkentin, J. D. (2007) Voltage-dependent anion channels are dispensable for mitochondrial-dependent cell death. Nat. Cell. Biol. 9, 550-555. https://doi.org/10.1038/ncb1575
  32. Kokoszka, J. E., Waymire, K. G., Levy, S. E., Sligh, J. E., Cai, J., Jones, D. P., MacGregor, G. R. and Wallace, D. C. (2004) The ADP/ATP translocator is not essential for the mitochondrial permeability transition pore. Nature 427, 461-465. https://doi.org/10.1038/nature02229
  33. Basso, E., Fante, L., Fowlkes, J., Petronilli, V., Forte, M. A. and Bernardi, P. (2005) Properties of the permeability transition pore in mitochondria devoid of Cyclophilin D. J. Biol. Chem. 280, 18558-18561. https://doi.org/10.1074/jbc.C500089200
  34. Baines, C. P., Kaiser, R. A., Purcell, N. H., Blair, N. S., Osinska, H., Hambleton, M. A., Brunskill, E. W., Sayen, M. R., Gottlieb, R. A., Dorn, G. W., Robbins, J. and Molkentin, J. D. (2005) Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature 434, 658-662. https://doi.org/10.1038/nature03434
  35. Nakagawa, T., Shimizu, S., Watanabe, T., Yamaguchi, O., Otsu, K., Yamagata, H., Inohara, H., Kubo, T. and Tsujimoto, Y. (2005) Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death. Nature 434, 652-658. https://doi.org/10.1038/nature03317
  36. Johnson, N., Khan, A., Virji, S., Ward, J. M. and Crompton, M. (1999) Import and processing of heart mitochondrial cyclophilin D. Eur. J. Biochem. 263, 353-359. https://doi.org/10.1046/j.1432-1327.1999.00490.x
  37. Kang, B. H. and Altieri, D. C. (2009) Compartmentalized cancer drug discovery targeting mitochondrial Hsp90 chaperones. Oncogene 28, 3681-3688. https://doi.org/10.1038/onc.2009.227
  38. Coller, H. A., Grandori, C., Tamayo, P., Colbert, T., Lander, E. S., Eisenman, R. N. and Golub, T. R. (2000) Expression analysis with oligonucleotide microarrays reveals that MYC regulates genes involved in growth, cell cycle, signaling, and adhesion. Proc. Natl. Acad. Sci. U.S.A. 97, 3260-3265. https://doi.org/10.1073/pnas.97.7.3260
  39. Putz, S. M., Vogiatzi, F., Stiewe, T. and Sickmann, A. (2010) Malignant transformation in a defined genetic background: proteome changes displayed by 2D-PAGE. Mol. Cancer 9, 254. https://doi.org/10.1186/1476-4598-9-254
  40. Leav, I., Plescia, J., Goel, H. L., Li, J., Jiang, Z., Cohen, R. J., Languino, L. R. and Altieri, D. C. (2010) Cytoprotective mitochondrial chaperone TRAP-1 as a novel molecular target in localized and metastatic prostate cancer. Am. J. Pathol. 176, 393-401. https://doi.org/10.2353/ajpath.2010.090521
  41. Kang, B. H., Xia, F., Pop, R., Dohi, T., Socolovsky, M. and Altieri, D. C. (2011) Developmental control of apoptosis by the immunophilin aryl hydrocarbon receptor-interacting protein (AIP) involves mitochondrial import of the survivin protein. J. Biol. Chem. 286, 16758-16767. https://doi.org/10.1074/jbc.M110.210120
  42. Pridgeon, J. W., Olzmann, J. A., Chin, L. S. and Li, L. (2007) PINK1 protects against oxidative stress by phosphorylating mitochondrial chaperone TRAP1. PLoS Biol. 5, e172. https://doi.org/10.1371/journal.pbio.0050172
  43. Trepel, J., Mollapour, M., Giaccone, G. and Neckers, L. (2010) Targeting the dynamic HSP90 complex in cancer. Nat. Rev. Cancer 10, 537-549. https://doi.org/10.1038/nrc2887
  44. Gatenby, R. A. and Gillies, R. J. (2004) Why do cancers have high aerobic glycolysis? Nat. Rev. Cancer 4, 891-899. https://doi.org/10.1038/nrc1478
  45. Costantino, E., Maddalena, F., Calise, S., Piscazzi, A., Tirino, V., Fersini, A., Ambrosi, A., Neri, V., Esposito, F. and Landriscina, M. (2009) TRAP1, a novel mitochondrial chaperone responsible for multi-drug resistance and protection from apoptosis in human colorectal carcinoma cells. Cancer Lett. 279, 39-46. https://doi.org/10.1016/j.canlet.2009.01.018
  46. Liu, D., Hu, J., Agorreta, J., Cesario, A., Zhang, Y., Harris, A. L., Gatter, K. and Pezzella, F. (2010) Tumor necrosis factor receptor-associated protein 1(TRAP1) regulates genes involved in cell cycle and metastases. Cancer Lett. 296, 194-205. https://doi.org/10.1016/j.canlet.2010.04.017
  47. Takemoto, K., Miyata, S., Takamura, H., Katayama, T. and Tohyama, M. (2011) Mitochondrial TRAP1 regulates the unfolded protein response in the endoplasmic reticulum. Neurochem. Int. 58, 880-887. https://doi.org/10.1016/j.neuint.2011.02.015
  48. Kang, B. H., Siegelin, M. D., Plescia, J., Raskett, C. M., Garlick, D. S., Dohi, T., Lian, J. B., Stein, G. S., Languino, L. R. and Altieri, D. C. (2010) Preclinical characterization of mitochondria-targeted small molecule hsp90 inhibitors, gamitrinibs, in advanced prostate cancer. Clin. Cancer Res. 16, 4779-4788. https://doi.org/10.1158/1078-0432.CCR-10-1818
  49. Kang, B. H., Tavecchio, M., Goel, H. L., Hsieh, C. C., Garlick, D. S., Raskett, C. M., Lian, J. B., Stein, G. S., Languino, L. R. and Altieri, D. C. (2011) Targeted inhibition of mitochondrial Hsp90 suppresses localised and metastatic prostate cancer growth in a genetic mouse model of disease. Br. J. Cancer 104, 629-634. https://doi.org/10.1038/bjc.2011.9
  50. Plescia, J., Salz, W., Xia, F., Pennati, M., Zaffaroni, N., Daidone, M. G., Meli, M., Dohi, T., Fortugno, P., Nefedova, Y., Gabrilovich, D. I., Colombo, G. and Altieri, D. C. (2005) Rational design of shepherdin, a novel anticancer agent. Cancer Cell 7, 457-468. https://doi.org/10.1016/j.ccr.2005.03.035
  51. Fulda, S., Galluzzi, L. and Kroemer, G. (2010) Targeting mitochondria for cancer therapy. Nat. Rev. Drug Discov. 9, 447-464. https://doi.org/10.1038/nrd3137

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