Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Targeting heat shock proteins in metastatic castration-resistant prostate cancer

Nature Reviews Urology volume 12, pages 26–36 (2015)Cite this article

Subjects

Key Points

  • Heat shock proteins (HSPs) are molecular chaperones that regulate protein homeostasis, signal transduction and transcriptional networks, and are key drivers of adaptive stress-response pathways in many malignancies

  • HSPs are highly expressed in many cancers, and subversion of their chaperone functions enables survival of malignant cells subjected to proteotoxic stress

  • HSPs are important in androgen receptor function (including ligand binding and nuclear trafficking), and many HSP client proteins modulate key signalling and transductional networks in castration-resistant prostate cancer (CRPC) cells

  • Extensive preclinical data have demonstrated the utility of targeting HSPs, including HSP90, HSP70, HSP27 and clusterin, in prostate cancer

  • Clinical development of HSP blockade as a therapeutic strategy in CRPC has been challenging, but antisense oligonucleotides targeting HSP27 and clusterin have proceeded to late-stage clinical trials

  • Integrating HSP blockade into the treatment paradigm for CRPC will require the development of potent, selective inhibitors of HSPs, and identification of rational combination strategies

Abstract

The survival of malignant cells is constantly threatened by a myriad of cellular insults. In the context of such proteotoxic stress, cancer cells activate cytoprotective adaptive pathways. Heat shock proteins (HSPs) are highly conserved molecular chaperones that are expressed at low levels under normal conditions, but upregulated by cellular stress. As molecular chaperones, HSPs control the stability and function of client proteins, preventing aggregation of misfolded proteins, facilitating intracellular protein trafficking, maintaining protein conformation to enable ligand binding, phosphorylating proteins in signalling complexes and degrading severely damaged proteins via the ubiquitin–proteasome pathway. A key client protein of several HSPs is the androgen receptor (AR). HSPs facilitate binding of dihydrotestosterone to the AR, and enhance AR-mediated transcriptional activity. The integral role of HSPs in AR function speaks to their potential utility as therapeutic targets in castration-resistant prostate cancer (CRPC), a disease state characterized by persistent activation of the androgen–AR axis. Inhibition of HSPs has the additional benefit of potentially modulating signalling and transcriptional networks that are associated with HSP client proteins in CRPC cells. As a consequence, HSPs represent highly attractive targets in the development of treatments for CRPC.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Heat shock proteins and the androgen receptor.

Similar content being viewed by others

References

  1. Calderwood, S. K. & Ciocca, D. R. Heat shock proteins: stress proteins with Janus-like properties in cancer. Int. J. Hyperthermia 24, 31–39 (2008).

    Article  CAS  PubMed  Google Scholar 

  2. Zoubeidi, A. & Gleave, M. Small heat shock proteins in cancer therapy and prognosis. Int. J. Biochem. Cell Biol. 44, 1646–1656 (2012).

    Article  CAS  PubMed  Google Scholar 

  3. Ischia, J. & So, A. I. The role of heat shock proteins in bladder cancer. Nat. Rev. Urol. 10, 386–395 (2013).

    Article  CAS  PubMed  Google Scholar 

  4. Ischia, J., Saad, F. & Gleave, M. The promise of heat shock protein inhibitors in the treatment of castration resistant prostate cancer. Curr. Opin. Urol. 23, 194–200 (2013).

    Article  PubMed  Google Scholar 

  5. Akerfelt, M., Morimoto, R. I. & Sistonen, L. Heat shock factors: integrators of cell stress, development and lifespan. Nat. Rev. Mol. Cell Biol. 11, 545–555 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Pirkkala, L., Nykänen, P. & Sistonen, L. Roles of the heat shock transcription factors in regulation of the heat shock response and beyond. FASEB J. 15, 1118–1131 (2001).

    Article  CAS  PubMed  Google Scholar 

  7. Whitesell, L. & Lindquist, S. L. HSP90 and the chaperoning of cancer. Nat. Rev. Cancer 5, 761–772 (2005).

    Article  CAS  PubMed  Google Scholar 

  8. Jego, G., Hazoumé, A., Seigneuric, R. & Garrido, C. Targeting heat shock proteins in cancer. Cancer Lett. 332, 275–285 (2013).

    Article  CAS  PubMed  Google Scholar 

  9. Cano, L. Q., Lavery, D. N. & Bevan, C. L. Mini-review: Foldosome regulation of androgen receptor action in prostate cancer. Mol. Cell. Endocrinol. 369, 52–62 (2013).

    Article  PubMed  CAS  Google Scholar 

  10. Fang, Y., Fliss, A. E., Robins, D. M. & Caplan, A. J. Hsp90 regulates androgen receptor hormone binding affinity in vivo. J. Biol. Chem. 271, 28697–28702 (1996).

    Article  CAS  PubMed  Google Scholar 

  11. Zoubeidi, A. et al. Cooperative interactions between androgen receptor (AR) and heat-shock protein 27 facilitate AR transcriptional activity. Cancer Res. 67, 10455–10465 (2007).

    Article  CAS  PubMed  Google Scholar 

  12. Ryan, C. J. & Tindall, D. J. Androgen receptor rediscovered: the new biology and targeting the androgen receptor therapeutically. J. Clin. Oncol. 29, 3651–3658 (2011).

    Article  CAS  PubMed  Google Scholar 

  13. Powers, M. V. & Workman, P. Targeting of multiple signalling pathways by heat shock protein 90 molecular chaperone inhibitors. Endocr. Relat. Cancer 13 (Suppl. 1), S125–S135 (2006).

    Article  CAS  PubMed  Google Scholar 

  14. Taipale, M., Jarosz, D. F. & Lindquist, S. HSP90 at the hub of protein homeostasis: emerging mechanistic insights. Nat. Rev. Mol. Cell Biol. 11, 515–528 (2010).

    Article  CAS  PubMed  Google Scholar 

  15. Mollapour, M. & Neckers, L. Post-translational modifications of Hsp90 and their contributions to chaperone regulation. Biochim. Biophys. Acta 1823, 648–655 (2012).

    Article  CAS  PubMed  Google Scholar 

  16. Ferraldeschi, R. et al. In vitro and in vivo antitumor activity of the next generation HSP90 inhibitor, AT13387, in both hormone-sensitive and castration-resistant prostate cancer models [abstract 2433]. Cancer Res. http://dx.doi.org/10.1158/1538-7445.AM2013-2433.

  17. Eskew, J. D. et al. Development and characterization of a novel C-terminal inhibitor of Hsp90 in androgen dependent and independent prostate cancer cells. BMC Cancer 11, 468 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. He, S. et al. Potent activity of the Hsp90 inhibitor ganetespib in prostate cancer cells irrespective of androgen receptor status or variant receptor expression. Int. J. Oncol. 42, 35–43 (2013).

    Article  CAS  PubMed  Google Scholar 

  19. Centenera, M. M. et al. Evidence for efficacy of new Hsp90 inhibitors revealed by ex vivo culture of human prostate tumors. Clin. Cancer Res. 18, 3562–3570 (2012).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  21. Solit, D. B. et al. 17-Allylamino-17-demethoxygeldanamycin induces the degradation of androgen receptor and HER-2/neu and inhibits the growth of prostate cancer xenografts. Clin. Cancer Res. 8, 986–993 (2002).

    CAS  PubMed  Google Scholar 

  22. Matthews, S. B. et al. Characterization of a novel novobiocin analogue as a putative C-terminal inhibitor of heat shock protein 90 in prostate cancer cells. Prostate 70, 27–36 (2010).

    Article  CAS  PubMed  Google Scholar 

  23. Lamoureux, F. et al. A novel HSP90 inhibitor delays castrate-resistant prostate cancer without altering serum PSA levels and inhibits osteoclastogenesis. Clin. Cancer Res. 17, 2301–2313 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Eccles, S. A. et al. NVP-AUY922: a novel heat shock protein 90 inhibitor active against xenograft tumor growth, angiogenesis, and metastasis. Cancer Res. 68, 2850–2860 (2008).

    Article  CAS  PubMed  Google Scholar 

  25. Hance, M. W. et al. Secreted Hsp90 is a novel regulator of the epithelial to mesenchymal transition (EMT) in prostate cancer. J. Biol. Chem. 287, 37732–37744 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Teng, Y., Ngoka, L., Mei, Y., Lesoon, L. & Cowell, J. K. HSP90 and HSP70 proteins are essential for stabilization and activation of WASF3 metastasis-promoting protein. J. Biol. Chem. 287, 10051–10059 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Alqawi, O., Moghaddas, M. & Singh, G. Effects of geldanamycin on HIF-1alpha mediated angiogenesis and invasion in prostate cancer cells. Prostate Cancer Prostatic Dis. 9, 126–135 (2006).

    Article  CAS  PubMed  Google Scholar 

  28. Mabjeesh, N. J. et al. Geldanamycin induces degradation of hypoxia-inducible factor 1alpha protein via the proteosome pathway in prostate cancer cells. Cancer Res. 62, 2478–2482 (2002).

    CAS  PubMed  Google Scholar 

  29. Vanaja, D. K., Mitchell, S. H., Toft, D. O. & Young, C. Y. Effect of geldanamycin on androgen receptor function and stability. Cell Stress Chaperones 7, 55–64 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Saporita, A. J., Ai, J. & Wang, Z. The Hsp90 inhibitor, 17-AAG, prevents the ligand-independent nuclear localization of androgen receptor in refractory prostate cancer cells. Prostate 67, 509–520 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. O'Malley, K. J. et al. Hsp90 inhibitor 17-AAG inhibits progression of LuCaP35 xenograft prostate tumors to castration resistance. Prostate 72, 1117–1123 (2012).

    Article  CAS  PubMed  Google Scholar 

  32. Chandarlapaty, S. et al. SNX2112, a synthetic heat shock protein 90 inhibitor, has potent antitumor activity against HER kinase-dependent cancers. Clin. Cancer Res. 14, 240–248 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Heath, E. I. et al. A phase II trial of 17-allylamino-17-demethoxygeldanamycin in patients with hormone-refractory metastatic prostate cancer. Clin. Cancer Res. 14, 7940–7946 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Pacey, S. et al. A phase I study of the heat shock protein 90 inhibitor alvespimycin (17-DMAG) given intravenously to patients with advanced solid tumors. Clin. Cancer Res. 17, 1561–1570 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Oh, W. K. et al. Multicenter phase II trial of the heat shock protein 90 inhibitor, retaspimycin hydrochloride (IPI-504), in patients with castration-resistant prostate cancer. Urology 78, 626–630 (2011).

    Article  PubMed  Google Scholar 

  36. Heath, E. I. et al. Phase II trial of single-agent ganetespib (STA-9090), a heat shock protein 90 (Hsp90) inhibitor in heavily pretreated patients with metastatic castration-resistant prostate cancer (mCRPC) post docetaxel-based chemotherapy: Results of a Prostate Cancer Clinical Trials Consortium (PCCTC) study [abstract 5085]. J. Clin. Oncol. 31 (Suppl.) (2013).

  37. Rajan, A. et al. A phase I study of PF-04929113 (SNX-5422), an orally bioavailable heat shock protein 90 inhibitor, in patients with refractory solid tumor malignancies and lymphomas. Clin. Cancer Res. 17, 6831–6839 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Mattos-Arruda, L. D. et al. Phase I dose-escalation, open-label study of HSP990 administered orally in adult patients with advanced solid malignancies [abstract 2561]. J. Clin. Oncol. 31 (Suppl.) (2013).

  39. Kang, B. H. et al. Preclinical characterization of mitochondria-targeted small molecule hsp90 inhibitors, gamitrinibs, in advanced prostate cancer. Clin. Cancer Res. 16, 4779–4788 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Lamoureux, F. et al. Suppression of heat shock protein 27 using OGX-427 induces endoplasmic reticulum stress and potentiates heat shock protein 90 inhibitors to delay castrate-resistant prostate cancer. Eur. Urol. 66, 145–155 (2014).

    Article  CAS  PubMed  Google Scholar 

  41. Lamoureux, F. et al. Clusterin inhibition using OGX-011 synergistically enhances Hsp90 inhibitor activity by suppressing the heat shock response in castrate-resistant prostate cancer. Cancer Res. 71, 5838–5849 (2011).

    Article  CAS  PubMed  Google Scholar 

  42. Ciocca, D. R., Arrigo, A. P. & Calderwood, S. K. Heat shock proteins and heat shock factor 1 in carcinogenesis and tumor development: an update. Arch. Toxicol. 87, 19–48 (2013).

    Article  CAS  PubMed  Google Scholar 

  43. Shatkina, L. et al. The cochaperone Bag-1L enhances androgen receptor action via interaction with the NH2-terminal region of the receptor. Mol. Cell. Biol. 23, 7189–7197 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Ren, A., Yan, G., You, B. & Sun, J. Down-regulation of mammalian sterile 20-like kinase 1 by heat shock protein 70 mediates cisplatin resistance in prostate cancer cells. Cancer Res. 68, 2266–2274 (2008).

    Article  CAS  PubMed  Google Scholar 

  45. Gibbons, N. B., Watson, R. W., Coffey, R. N., Brady, H. P. & Fitzpatrick, J. M. Heat-shock proteins inhibit induction of prostate cancer cell apoptosis. Prostate 45, 58–65 (2000).

    Article  CAS  PubMed  Google Scholar 

  46. Roigas, J., Wallen, E. S., Loening, S. A. & Moseley, P. L. Effects of combined treatment of chemotherapeutics and hyperthermia on survival and the regulation of heat shock proteins in Dunning R3327 prostate carcinoma cells. Prostate 34, 195–202 (1998).

    Article  CAS  PubMed  Google Scholar 

  47. Gabai, V. L., Budagova, K. R. & Sherman, M. Y. Increased expression of the major heat shock protein Hsp72 in human prostate carcinoma cells is dispensable for their viability but confers resistance to a variety of anticancer agents. Oncogene 24, 3328–3338 (2005).

    Article  CAS  PubMed  Google Scholar 

  48. Koya, K. et al. MKT-077, a novel rhodacyanine dye in clinical trials, exhibits anticarcinoma activity in preclinical studies based on selective mitochondrial accumulation. Cancer Res. 56, 538–543 (1996).

    CAS  PubMed  Google Scholar 

  49. Britten, C. D. et al. A phase I and pharmacokinetic study of the mitochondrial-specific rhodacyanine dye analog MKT 077. Clin. Cancer Res. 6, 42–49 (2000).

    CAS  PubMed  Google Scholar 

  50. Parcellier, A. et al. Small heat shock proteins HSP27 and alphaB-crystallin: cytoprotective and oncogenic functions. Antioxid. Redox Signal. 7, 404–413 (2005).

    Article  CAS  PubMed  Google Scholar 

  51. Rocchi, P. et al. Increased Hsp27 after androgen ablation facilitates androgen-independent progression in prostate cancer via signal transducers and activators of transcription 3-mediated suppression of apoptosis. Cancer Res. 65, 11083–11093 (2005).

    Article  CAS  PubMed  Google Scholar 

  52. Andrieu, C. et al. Heat shock protein 27 confers resistance to androgen ablation and chemotherapy in prostate cancer cells through eIF4E. Oncogene 29, 1883–1896 (2010).

    Article  CAS  PubMed  Google Scholar 

  53. Baylot, V. et al. Targeting TCTP as a new therapeutic strategy in castration-resistant prostate cancer. Mol. Ther. 20, 2244–2256 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Zoubeidi, A. et al. Hsp27 promotes insulin-like growth factor-I survival signaling in prostate cancer via p90Rsk-dependent phosphorylation and inactivation of BAD. Cancer Res. 70, 2307–2317 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Hayashi, N. et al. Hsp27 silencing coordinately inhibits proliferation and promotes Fas-induced apoptosis by regulating the PEA-15 molecular switch. Cell Death Differ. 19, 990–1002 (2012).

    Article  CAS  PubMed  Google Scholar 

  56. Xu, L., Chen, S. & Bergan, R. C. MAPKAPK2 and HSP27 are downstream effectors of p38 MAP kinase-mediated matrix metalloproteinase type 2 activation and cell invasion in human prostate cancer. Oncogene 25, 2987–2998 (2006).

    Article  CAS  PubMed  Google Scholar 

  57. Shiota, M. et al. Hsp27 regulates epithelial mesenchymal transition, metastasis, and circulating tumor cells in prostate cancer. Cancer Res. 73, 3109–3119 (2013).

    Article  CAS  PubMed  Google Scholar 

  58. Razandi, M., Pedram, A. & Levin, E. R. Heat shock protein 27 is required for sex steroid receptor trafficking to and functioning at the plasma membrane. Mol. Cell. Biol. 30, 3249–3261 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Bubendorf, L. et al. Hormone therapy failure in human prostate cancer: analysis by complementary DNA and tissue microarrays. J. Natl Cancer Inst. 91, 1758–1764 (1999).

    Article  CAS  PubMed  Google Scholar 

  60. Cornford, P. A. et al. Heat shock protein expression independently predicts clinical outcome in prostate cancer. Cancer Res. 60, 7099–7105 (2000).

    CAS  PubMed  Google Scholar 

  61. Garrido, C. et al. Heat shock protein 27 enhances the tumorigenicity of immunogenic rat colon carcinoma cell clones. Cancer Res. 58, 5495–5499 (1998).

    CAS  PubMed  Google Scholar 

  62. Rocchi, P. et al. Heat shock protein 27 increases after androgen ablation and plays a cytoprotective role in hormone-refractory prostate cancer. Cancer Res. 64, 6595–6602 (2004).

    Article  CAS  PubMed  Google Scholar 

  63. Foster, C. S. et al. Hsp-27 expression at diagnosis predicts poor clinical outcome in prostate cancer independent of ETS-gene rearrangement. Br. J. Cancer 101, 1137–1144 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Zoubeidi, A. et al. Hsp27 promotes insulin-like growth factor-I survival signaling in prostate cancer via p90Rsk-dependent phosphorylation and inactivation of BAD. Cancer Res. 70, 2307–2317 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Aloy, M. T. et al. Protective role of Hsp27 protein against gamma radiation-induced apoptosis and radiosensitization effects of Hsp27 gene silencing in different human tumor cells. Int. J. Radiat. Oncol. Biol. Phys. 70, 543–553 (2008).

    Article  CAS  PubMed  Google Scholar 

  66. Zielinski, R. & Chi, K. N. Custirsen (OGX-011): a second-generation antisense inhibitor of clusterin in development for the treatment of prostate cancer. Future Oncol. 8, 1239–1251 (2012).

    Article  CAS  PubMed  Google Scholar 

  67. Kumano, M. et al. Cotargeting stress-activated Hsp27 and autophagy as a combinatorial strategy to amplify endoplasmic reticular stress in prostate cancer. Mol. Cancer Ther. 11, 1661–1671 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Hotte, S. J. et al. Phase I trial of OGX-427, a 2′methoxyethyl antisense oligonucleotide (ASO), against heat shock protein 27 (Hsp27): Final results [abstract 3077]. J. Clin. Oncol. 28 (Suppl.) (2010).

  69. Chi, K. et al. A randomized phase II study of OGX-427 plus prednisone (P) versus P alone in patients (pts) with metastatic castration resistant prostate cancer (CRPC) [abstract 4514]. J. Clin. Oncol. 30 (Suppl.) (2012).

  70. Loison, F. et al. Up-regulation of the clusterin gene after proteotoxic stress: implication of HSF1-HSF2 heterocomplexes. Biochem. J. 395, 223–231 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Cochrane, D. R., Wang, Z., Muramaki, M., Gleave, M. E. & Nelson, C. C. Differential regulation of clusterin and its isoforms by androgens in prostate cells. J. Biol. Chem. 282, 2278–2287 (2007).

    Article  CAS  PubMed  Google Scholar 

  72. Shiota, M. et al. Clusterin is a critical downstream mediator of stress-induced YB-1 transactivation in prostate cancer. Mol. Cancer Res. 9, 1755–1766 (2011).

    Article  CAS  PubMed  Google Scholar 

  73. Matsumoto, H. et al. Cotargeting androgen receptor and clusterin delays castrate-resistant prostate cancer progression by inhibiting adaptive stress response and AR stability. Cancer Res. 73, 5206–5217 (2013).

    Article  CAS  PubMed  Google Scholar 

  74. Montpetit, M. L., Lawless, K. R. & Tenniswood, M. Androgen-repressed messages in the rat ventral prostate. Prostate 8, 25–36 (1986).

    Article  CAS  PubMed  Google Scholar 

  75. Miyake, H., Nelson, C., Rennie, P. S. & Gleave, M. E. Testosterone-repressed prostate message-2 is an antiapoptotic gene involved in progression to androgen independence in prostate cancer. Cancer Res. 60, 170–176 (2000).

    CAS  PubMed  Google Scholar 

  76. Zhang, H. et al. Clusterin inhibits apoptosis by interacting with activated Bax. Nat. Cell Biol. 7, 909–915 (2005).

    Article  CAS  PubMed  Google Scholar 

  77. Ammar, H. & Closset, J. L. Clusterin activates survival through the phosphatidylinositol 3-kinase/Akt pathway. J. Biol. Chem. 283, 12851–12861 (2008).

    Article  CAS  PubMed  Google Scholar 

  78. Zhong, B. et al. Induction of clusterin by AKT--role in cytoprotection against docetaxel in prostate tumor cells. Mol. Cancer Ther. 9, 1831–1841 (2010).

    Article  CAS  PubMed  Google Scholar 

  79. Li, N., Zoubeidi, A., Beraldi, E. & Gleave, M. E. GRP78 regulates clusterin stability, retrotranslocation and mitochondrial localization under ER stress in prostate cancer. Oncogene 32, 1933–1942 (2013).

    Article  CAS  PubMed  Google Scholar 

  80. Shiota, M. et al. Clusterin mediates TGF-beta-induced epithelial-mesenchymal transition and metastasis via Twist1 in prostate cancer cells. Cancer Res. 72, 5261–5272 (2012).

    Article  CAS  PubMed  Google Scholar 

  81. Lenferink, A. E. et al. Transcriptome profiling of a TGF-beta-induced epithelial-to-mesenchymal transition reveals extracellular clusterin as a target for therapeutic antibodies. Oncogene 29, 831–844 (2010).

    Article  CAS  PubMed  Google Scholar 

  82. Lee, K. B. et al. Clusterin, a novel modulator of TGF-beta signaling, is involved in Smad2/3 stability. Biochem. Biophys. Res. Commun. 366, 905–909 (2008).

    Article  CAS  PubMed  Google Scholar 

  83. Chou, T. Y. et al. Clusterin silencing in human lung adenocarcinoma cells induces a mesenchymal-to-epithelial transition through modulating the ERK/Slug pathway. Cell. Signal. 21, 704–711 (2009).

    Article  CAS  PubMed  Google Scholar 

  84. Bhutia, S. K. et al. mda-7/IL-24 differentially regulates soluble and nuclear clusterin in prostate cancer. J. Cell. Physiol. 227, 1805–1813 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Song, H. et al. Loss of Nkx3.1 leads to the activation of discrete downstream target genes during prostate tumorigenesis. Oncogene 28, 3307–3319 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Steinberg, J. et al. Intracellular levels of SGP-2 (Clusterin) correlate with tumor grade in prostate cancer. Clin. Cancer Res. 3, 1707–1711 (1997).

    CAS  PubMed  Google Scholar 

  87. July, L. V. et al. Clusterin expression is significantly enhanced in prostate cancer cells following androgen withdrawal therapy. Prostate 50, 179–188 (2002).

    Article  CAS  PubMed  Google Scholar 

  88. Miyake, H. et al. Enhanced expression of the secreted form of clusterin following neoadjuvant hormonal therapy as a prognostic predictor in patients undergoing radical prostatectomy for prostate cancer. Oncol. Rep. 14, 1371–1375 (2005).

    CAS  PubMed  Google Scholar 

  89. Girard, F. P. et al. Detecting soluble clusterin in in-vitro and in-vivo models of prostate cancer. Neoplasma 57, 488–493 (2010).

    Article  CAS  PubMed  Google Scholar 

  90. Gleave, M. E. et al. Use of antisense oligonucleotides targeting the antiapoptotic gene, clusterin/testosterone-repressed prostate message 2, to enhance androgen sensitivity and chemosensitivity in prostate cancer. Urology 58, 39–49 (2001).

    Article  CAS  PubMed  Google Scholar 

  91. Miyake, H., Chi, K. N. & Gleave, M. E. Antisense TRPM-2 oligodeoxynucleotides chemosensitize human androgen-independent PC-3 prostate cancer cells both in vitro and in vivo. Clin. Cancer Res. 6, 1655–1663 (2000).

    CAS  PubMed  Google Scholar 

  92. Miyake, H., Nelson, C., Rennie, P. S. & Gleave, M. E. Acquisition of chemoresistant phenotype by overexpression of the antiapoptotic gene testosterone-repressed prostate message-2 in prostate cancer xenograft models. Cancer Res. 60, 2547–2554 (2000).

    CAS  PubMed  Google Scholar 

  93. Sowery, R. D. et al. Clusterin knockdown using the antisense oligonucleotide OGX-011 re-sensitizes docetaxel-refractory prostate cancer PC-3 cells to chemotherapy. BJU Int. 102, 389–397 (2008).

    Article  CAS  PubMed  Google Scholar 

  94. Trougakos, I. P., So, A., Jansen, B., Gleave, M. E. & Gonos, E. S. Silencing expression of the clusterin/apolipoprotein j gene in human cancer cells using small interfering RNA induces spontaneous apoptosis, reduced growth ability, and cell sensitization to genotoxic and oxidative stress. Cancer Res. 64, 1834–1842 (2004).

    Article  CAS  PubMed  Google Scholar 

  95. Zellweger, T. et al. Enhanced radiation sensitivity in prostate cancer by inhibition of the cell survival protein clusterin. Clin. Cancer Res. 8, 3276–3284 (2002).

    CAS  PubMed  Google Scholar 

  96. Chi, K. N. et al. A phase I pharmacokinetic and pharmacodynamic study of OGX-011, a 2′-methoxyethyl antisense oligonucleotide to clusterin, in patients with localized prostate cancer. J. Natl Cancer Inst. 97, 1287–1296 (2005).

    Article  CAS  PubMed  Google Scholar 

  97. Chi, K. N. et al. A phase I study of OGX-011, a 2′-methoxyethyl phosphorothioate antisense to clusterin, in combination with docetaxel in patients with advanced cancer. Clin. Cancer Res. 14, 833–839 (2008).

    Article  CAS  PubMed  Google Scholar 

  98. Chi, K. N. et al. Randomized phase II study of docetaxel and prednisone with or without OGX-011 in patients with metastatic castration-resistant prostate cancer. J. Clin. Oncol. 28, 4247–4254 (2010).

    Article  CAS  PubMed  Google Scholar 

  99. Teva and OncoGenex announce top-line survival results of phase III SYNERGY trial evaluating custirsen in combination with first-line docetaxel and prednisone for metastatic castrate-resistant prostate cancer. Teva Pharmaceutical Industries Ltd [online], (2014).

  100. Saad, F. et al. Randomized phase II trial of Custirsen (OGX-011) in combination with docetaxel or mitoxantrone as second-line therapy in patients with metastatic castrate-resistant prostate cancer progressing after first-line docetaxel: CUOG trial P-06c. Clin. Cancer Res. 17, 5765–5773 (2011).

    Article  CAS  PubMed  Google Scholar 

  101. Kole, R., Krainer, A. R. & Altman, S. RNA therapeutics: beyond RNA interference and antisense oligonucleotides. Nat. Rev. Drug Discov. 11, 125–140 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Stephanou, A. & Latchman, D. S. Transcriptional modulation of heat-shock protein gene expression. Biochem. Res. Int. 2011, 238601 (2011).

    Article  PubMed  CAS  Google Scholar 

  103. Morimoto, R. I. & Santoro, M. G. Stress-inducible responses and heat shock proteins: new pharmacologic targets for cytoprotection. Nat. Biotechnol. 16, 833–838 (1998).

    Article  CAS  PubMed  Google Scholar 

  104. Tsan, M. F. & Gao, B. Heat shock protein and innate immunity. Cell. Mol. Immunol. 1, 274–279 (2004).

    CAS  PubMed  Google Scholar 

  105. Lanneau, D., de Thonel, A., Maurel, S., Didelot, C. & Garrido, C. Apoptosis versus cell differentiation: role of heat shock proteins HSP90, HSP70 and HSP27. Prion 1, 53–60 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medical Oncology, British Columbia Cancer Agency, 600 West 10th Avenue, Vancouver, V5Z 4E6, BC, Canada

    Arun A. Azad & Kim N. Chi

  2. The Vancouver Prostate Centre, 2775 Laurel Street, 6th Floor, Vancouver, V5Z 1M9, BC, Canada

    Amina Zoubeidi & Martin E. Gleave

Authors
  1. Arun A. Azad
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Amina Zoubeidi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Martin E. Gleave
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kim N. Chi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

A.A.A., A.Z. and K.N.C. researched data for the article. All authors made a substantial contribution to discussion of content. A.A.A. and A.Z. wrote the article. All authors contributed to review and editing of the manuscript before submission.

Corresponding author

Correspondence to Kim N. Chi.

Ethics declarations

Competing interests

A.A.A. declares honoraria from Janssen and receipt of research funding from Astellas. M.E.G. is listed as inventor on patent applications OGX 011 and OGX 427, submitted by the University of British Columbia, and licensed to OncoGenex Technologies, in which M.E.G. is a founding shareholder. K.N.C. declares receipt of research funding from Astellas, Janssen, Novartis and OncoGenex Technologies, and consultancy for Amgen, Astellas, Bayer, Janssen, Millennium, Novartis and Sanofi. A.Z. declares no competing interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Azad, A., Zoubeidi, A., Gleave, M. et al. Targeting heat shock proteins in metastatic castration-resistant prostate cancer. Nat Rev Urol 12, 26–36 (2015). https://doi.org/10.1038/nrurol.2014.320

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrurol.2014.320

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing