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:

The role of heat shock proteins in bladder cancer

Nature Reviews Urology volume 10, pages 386–395 (2013)Cite this article

Subjects

Abstract

Heat shock proteins (HSPs) and clusterin (another chaperone protein with HSP-like properties) are present in normal cells and are upregulated by cellular stressors such as hyperthermia, hypoxia, and cytotoxic agents. HSPs are overexpressed in a wide range of cancers. Cancer cells are in a constant state of proteotoxic stress and exploit the HSPs to protect themselves against the toxic effects of aberrant oncoproteins, genomic instability, hypoxia, and acidosis. In many patients with cancer, high levels of HSPs are associated with poor prognosis and treatment resistance as these proteins protect tumour cells from therapeutic stressors such as androgen or oestrogen withdrawal, radiation, and cytotoxic chemotherapy. Differences in the expression levels of HSPs in bladder cancers compared with normal urothelium have led to HSPs being investigated as diagnostic and prognostic biomarkers. Evidence suggests that HSPs are important modulators of the immune system and have a role in BCG-stimulated regression of urothelial cancers. New bladder cancer treatment strategies that target HSPs are being investigated and could have a synergistic role with modern radiotherapy and chemotherapy regimens. A combination of OGX-427 (an antisense oligonucleotide that targets HSP27), gemcitabine, and cisplatin is currently being investigated in a phase II trial of patients with advanced bladder cancer.

Key Points

  • Heat shock proteins (HSPs) and clusterin are important for normal cellular homeostasis but are subverted by cancers to protect them from the toxic effects of oncoprotein aggregation, chemotherapy, and radiotherapy

  • Differences in the expression of HSPs in normal urothelium compared with bladder cancer tissue suggest that HSPs could have roles as diagnostic and prognostic biomarkers

  • HSPs have an immunomodulatory role and are involved in BCG-stimulated regression of urothelial cancers

  • New bladder cancer treatment strategies that target HSPs could have a synergistic role when combined with modern radiotherapy and chemotherapy regimens

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: Regulation of cell death pathways by HSPs, which are upregulated by cellular stressors such as hyperthermia or local hypoxia and acidosis.

Similar content being viewed by others

References

  1. Hartl, F. U. & Hayer-Hartl, M. Converging concepts of protein folding in vitro and in vivo. Nat. Struct. Mol. Biol. 16, 574–581 (2009).

  2. Doyle, S. M. Asymmetric deceleration of ClpB or Hsp104 ATPase activity unleashes protein-remodeling activity. Nat. Struct. Mol. Biol. 14, 114–122 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. McClellan, A. J., Tam, S., Kaganovich, D. & Frydman, J. Protein quality control: chaperones culling corrupt conformations. Nat. Cell. Biol. 7, 736–741 (2005).

    Article  CAS  PubMed  Google Scholar 

  4. 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 

  5. Kaufmann, S. H. Heat shock proteins and the immune response. Immunol. Today 11, 129–136 (1990).

    Article  CAS  PubMed  Google Scholar 

  6. Li, Z., Menoret, A. & Srivastava, P. Roles of heat-shock proteins in antigen presentation and cross-presentation. Curr. Opin. Immunol. 14, 45–51 (2002).

    Article  CAS  PubMed  Google Scholar 

  7. Harada, M., Kimura, G. & Nomoto, K. Heat shock proteins and the antitumor T cell response. Biotherapy 10, 229–235 (1998).

    Article  CAS  PubMed  Google Scholar 

  8. Calderwood, S. K., Khaleque, M. A., Sawyer, D. B. & Ciocca, D. R. Heat shock proteins in cancer: chaperones of tumorigenesis. Trends Biochem. Sci. 31, 164–172 (2006).

    Article  CAS  PubMed  Google Scholar 

  9. Parsell, D. A. & Lindquist, S. The function of heat-shock proteins in stress tolerance: degradation and reactivation of damaged proteins. Ann. Rev. Genet. 27, 437–496 (1993).

    Article  CAS  PubMed  Google Scholar 

  10. 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 

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

    Article  CAS  PubMed  Google Scholar 

  12. Oesterreich, S. The small heat shock protein hsp27 is correlated with growth and drug resistance in human breast cancer cell lines. Cancer Res. 53, 4443–4448 (1993).

    CAS  PubMed  Google Scholar 

  13. 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 

  14. Ciocca, D. R. & Calderwood, S. K. Heat shock proteins in cancer: diagnostic, prognostic, predictive, and treatment implications. Cell Stress Chaperones 10, 86–103 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Garrido, C. et al. Heat shock proteins 27 and 70: anti-apoptotic proteins with tumorigenic properties. Cell Cycle 5, 2592–2601 (2006).

    Article  CAS  PubMed  Google Scholar 

  16. Karapanagiotou, E. M., Syrigos, K. & Saif, M. W. Heat shock protein inhibitors and vaccines as new agents in cancer treatment. Expert Opin. Investig. Drugs 18, 161–174 (2009).

    Article  CAS  PubMed  Google Scholar 

  17. Conroy, S. E. Antibodies to heat-shock protein 27 are associated with improved survival in patients with breast cancer. Br. J. Cancer 77, 1875–1879 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Arts, H. J. Heat-shock-protein-27 (hsp27) expression in ovarian carcinoma: relation in response to chemotherapy and prognosis. Int. J. Cancer 84, 234–238 (1999).

    Article  CAS  PubMed  Google Scholar 

  19. Bubendorf, L. 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 

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

    CAS  PubMed  Google Scholar 

  21. Ehrenfried, J. A., Herron, B. E., Townsend, C. M. Jr & Evers, B. M. Heat shock proteins are differentially expressed in human gastrointestinal cancers. Surg. Oncol. 4, 197–203 (1995).

    Article  CAS  PubMed  Google Scholar 

  22. Thomas, X. Expression of heat-shock proteins is associated with major adverse prognostic factors in acute myeloid leukemia. Leuk. Res. 29, 1049–1058 (2005).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  24. Rocchi, P. 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 

  25. Zoubeidi, A. 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 

  26. Mayer, M. P. & Bukau, B. Hsp70 chaperones: cellular functions and molecular mechanism. Cell. Mol. Life Sci. 62, 670–684 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Picard, D. Heat-shock protein 90, a chaperone for folding and regulation. Cell. Mol. Life Sci. 59, 1640–1648 (2002).

    Article  CAS  PubMed  Google Scholar 

  28. Basso, A. D. Akt forms an intracellular complex with heat shock protein 90 (Hsp90) and Cdc37 and is destabilized by inhibitors of Hsp90 function. J. Biol. Chem. 277, 39858–39866 (2002).

    Article  CAS  PubMed  Google Scholar 

  29. Lee, H., Choi, S. K. & Ro, J. Y. Overexpression of DJ-1 and HSP90alpha, and loss of PTEN associated with invasive urothelial carcinoma of urinary bladder: Possible prognostic markers. Oncol. Lett. 3, 507–512 (2012).

    PubMed  Google Scholar 

  30. 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 

  31. Pick, E. High HSP90 expression is associated with decreased survival in breast cancer. Cancer Res. 67, 2932–2937 (2007).

    Article  CAS  PubMed  Google Scholar 

  32. McCarthy, M. M. HSP90 as a marker of progression in melanoma. Ann. Oncol. 19, 590–594 (2008).

    Article  CAS  PubMed  Google Scholar 

  33. Rodina, A. Selective compounds define Hsp90 as a major inhibitor of apoptosis in small-cell lung cancer. Nat. Chem. Biol. 3, 498–507 (2007).

    Article  CAS  PubMed  Google Scholar 

  34. Giaginis, C. et al. Heat Shock Protein-27, -60 and -90 expression in gastric cancer: association with clinicopathological variables and patient survival. BMC Gastroenterol. 9, 14 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Lattouf, J. B., Srinivasan, R., Pinto, P. A., Linehan, W. M. & Neckers, L. Mechanisms of disease: the role of heat-shock protein 90 in genitourinary malignancy. Nat. Clin. Pract. Urol. 3, 590–601 (2006).

    Article  CAS  PubMed  Google Scholar 

  36. Solit, D. B. & Chiosis, G. Development and application of Hsp90 inhibitors. Drug Discov. Today 13, 38–43 (2008).

    Article  CAS  PubMed  Google Scholar 

  37. Chiosis, G. & Neckers, L. Tumor selectivity of Hsp90 inhibitors: the explanation remains elusive. ACS Chem. Biol. 1, 279–284 (2006).

    Article  CAS  PubMed  Google Scholar 

  38. Lebret, T. Heat shock proteins HSP27, HSP60, HSP70, and HSP90: expression in bladder carcinoma. Cancer 98, 970–977 (2003).

    Article  CAS  PubMed  Google Scholar 

  39. Lebret, T. HSP90 expression: a new predictive factor for BCG response in stage Ta-T1 grade 3 bladder tumours. Eur. Urol. 51, 161–167 (2007).

    Article  CAS  PubMed  Google Scholar 

  40. Romanucci, M. Expression of heat shock proteins in premalignant and malignant urothelial lesions of bovine urinary bladder. Cell Stress Chaperones 17, 683–692 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Scieglinska, D., Piglowski, W., Chekan, M., Mazurek, A. & Krawczyk, Z. Differential expression of HSPA1 and HSPA2 proteins in human tissues; tissue microarray-based immunohistochemical study. Histochem. Cell Biol. 135, 337–350 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Vydra, N. The expression pattern of the 70-kDa heat shock protein Hspa2 in mouse tissues. Histochem. Cell Biol. 132, 319–330 (2009).

    Article  CAS  PubMed  Google Scholar 

  43. Takashi, M., Katsuno, S., Sakata, T., Ohshima, S. & Kato, K. Different concentrations of two small stress proteins, alphaB crystallin and HSP27 in human urological tumor tissues. Urol. Res. 26, 395–399 (1998).

    Article  CAS  PubMed  Google Scholar 

  44. El-Meghawry El-Kenawy, A., El-Kott, A. F. & Hasan, M. S. Heat shock protein expression independently predicts survival outcome in schistosomiasis-associated urinary bladder cancer. Int. J. Biol. Markers 23, 214–218 (2008).

    Article  CAS  PubMed  Google Scholar 

  45. Kim, H. J., Sohng, I., Hwang, C. H. & Park, J. Y. Cytokeratin-20 and seminal vesicle secretory protein VI as possible marker proteins in urinary bladder preneoplastic lesions induced by N-butyl-N-(4-hydroxybutyl) nitrosamine. Int. J. Urol. 13, 142–147 (2006).

    Article  CAS  PubMed  Google Scholar 

  46. Matsui, Y. Intravesical combination treatment with antisense oligonucleotides targeting heat shock protein-27 and HTI-286 as a novel strategy for high-grade bladder cancer. Mol. Cancer Ther. 8, 2402–2411 (2009).

    Article  CAS  PubMed  Google Scholar 

  47. So, A., Rocchi, P. & Gleave, M. Antisense oligonucleotide therapy in the management of bladder cancer. Curr. Opin. Urol. 15, 320–327 (2005).

    Article  PubMed  Google Scholar 

  48. Behnsawy, H. M., Miyake, H., Kusuda, Y. & Fujisawa, M. Small interfering RNA targeting heat shock protein 70 enhances chemosensitivity in human bladder cancer cells. Urol. Oncol. http://dx.doi.org/10.1016/j.urolonc.2011.07.007

  49. He, L. F. Heat shock protein 70 expression in relation to apoptosis in primary bladder transitional cell carcinoma. Chin Med. J. (Engl.) 118, 2093–2096 (2005).

    Google Scholar 

  50. Syrigos, K. N. Clinical significance of heat shock protein-70 expression in bladder cancer. Urology 61, 677–680 (2003).

    Article  PubMed  Google Scholar 

  51. Garg, M. Heat-shock protein 70-2 (HSP70-2) expression in bladder urothelial carcinoma is associated with tumour progression and promotes migration and invasion. Eur. J. Cancer 46, 207–215 (2010).

    Article  CAS  PubMed  Google Scholar 

  52. Kamishima, T. Carcinosarcoma of the urinary bladder: expression of epithelial markers and different expression of heat shock proteins between epithelial and sarcomatous elements. Pathol. Int. 47, 166–173 (1997).

    Article  CAS  PubMed  Google Scholar 

  53. Cardillo, M. R., Sale, P. & Di Silverio, F. Heat shock protein-90, IL-6 and IL-10 in bladder cancer. Anticancer Res. 20, 4579–4583 (2000).

    CAS  PubMed  Google Scholar 

  54. Sheng, K. H., Yao, Y. C., Chuang, S. S., Wu, H. & Wu, T. F. Search for the tumor-related proteins of transition cell carcinoma in Taiwan by proteomic analysis. Proteomics 6, 1058–1065 (2006).

    Article  CAS  PubMed  Google Scholar 

  55. Chen, C. J., Chuang, Y. C., Lin, T. M. & Wu, H. Y. Malignant neoplasms among residents of a blackfoot disease-endemic area in Taiwan: high-arsenic artesian well water and cancers. Cancer Res. 45, 5895–5899 (1985).

    Google Scholar 

  56. Liu, J. Stress-related gene expression in mice treated with inorganic arsenicals. Toxicol. Sci. 61, 314–320 (2001).

    Article  CAS  PubMed  Google Scholar 

  57. Margel, D., Pevsner-Fischer, M., Baniel, J., Yossepowitch, O. & Cohen, I. R. Stress proteins and cytokines are urinary biomarkers for diagnosis and staging of bladder cancer. Eur. Urol. 59, 113–119 (2011).

    Article  CAS  PubMed  Google Scholar 

  58. Thanner, F. Heat shock protein 27 is associated with decreased survival in node-negative breast cancer patients. Anticancer Res. 25, 1649–1653 (2005).

    CAS  PubMed  Google Scholar 

  59. Love, S. & King, R. J. A 27 kDa heat shock protein that has anomalous prognostic powers in early and advanced breast cancer. Br. J. Cancer 69, 743–748 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Oesterreich, S. The small heat shock protein HSP27 is not an independent prognostic marker in axillary lymph node-negative breast cancer patients. Clin. Cancer Res. 2, 1199–1206 (1996).

    CAS  PubMed  Google Scholar 

  61. Thor, A. et al. Stress response protein (srp-27) determination in primary human breast carcinomas: clinical, histologic, and prognostic correlations. J. Natl Cancer Inst. 83, 170–178 (1991).

    Article  CAS  PubMed  Google Scholar 

  62. Storm, F. K., Mahvi, D. M. & Gilchrist, K. W. Hsp27 has no diagnostic or prognostic significance in prostate or bladder cancers. Urology 42, 379–382 (1993).

    Article  CAS  PubMed  Google Scholar 

  63. Brandau, S. & Bohle, A. Bladder cancer. I. Molecular and genetic basis of carcinogenesis. Eur. Urol. 39, 491–497 (2001).

    Article  CAS  PubMed  Google Scholar 

  64. Ardelt, P. U. et al. Reactive antibodies against bacillus Calmette-Guerin heat-shock protein-65 potentially predict the outcome of immunotherapy for high-grade transitional cell carcinoma of the bladder. Cancer 116, 600–609 (2010).

    Article  CAS  PubMed  Google Scholar 

  65. Zlotta, A. R. Humoral response against heat shock proteins and other mycobacterial antigens after intravesical treatment with bacille Calmette-Guerin (BCG) in patients with superficial bladder cancer. Clin. Exp. Immunol. 109, 157–165 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Kassem, H., Sangar, V., Cowan, R., Clarke, N. & Margison, G. P. A potential role of heat shock proteins and nicotinamide N-methyl transferase in predicting response to radiation in bladder cancer. Int. J. Cancer 101, 454–460 (2002).

    Article  CAS  PubMed  Google Scholar 

  67. Kamada, M. Hsp27 knockdown using nucleotide-based therapies inhibit tumor growth and enhance chemotherapy in human bladder cancer cells. Mol. Cancer Ther. 6, 299–308 (2007).

    Article  CAS  PubMed  Google Scholar 

  68. Richards, E., Begum, T. & Masters, J. Thermotolerance and sensitivity of human cancer cells to cisplatin and doxorubicin. Int. J. Oncol. 8, 1265–1271 (1996).

    CAS  PubMed  Google Scholar 

  69. Urushibara, M. HSP60 may predict good pathological response to neoadjuvant chemoradiotherapy in bladder cancer. J. Clin. Oncol. 37, 56–61 (2007).

    Google Scholar 

  70. Konstantakou, E. G. Human bladder cancer cells undergo cisplatin-induced apoptosis that is associated with p53-dependent and p53-independent responses. Int. J. Oncol. 35, 401–416 (2009).

    CAS  PubMed  Google Scholar 

  71. Gleave, M. & Miyake, H. Use of antisense oligonucleotides targeting the cytoprotective gene, clusterin, to enhance androgen- and chemo-sensitivity in prostate cancer. World J. Urol. 23, 38–46 (2005).

    Article  CAS  PubMed  Google Scholar 

  72. Hadaschik, B. A. Intravesically administered antisense oligonucleotides targeting heat-shock protein-27 inhibit the growth of non-muscle-invasive bladder cancer. BJU Int. 102, 610–616 (2008).

    Article  CAS  PubMed  Google Scholar 

  73. So, A., Black, P., Chi, K., Hurtado-Col, A. & Gleave, M. In ASCO Vol. 30, Suppl. 5 Abstract no. 389 (J. Clin. Oncol., USA, 2012).

    Google Scholar 

  74. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  75. Chen, N. G. Proteomic approaches to study epigallocatechin gallate-provoked apoptosis of TSGH-8301 human urinary bladder carcinoma cells: roles of AKT and heat shock protein 27-modulated intrinsic apoptotic pathways. Oncol. Rep. 26, 939–947 (2011).

    CAS  PubMed  Google Scholar 

  76. He, L. F. Enhanced sensitivity to mitomycin C by abating heat shock protein 70 expression in human bladder cancer cell line of BIU-87. Chin. Med. J. (Engl.) 118, 1965–1972 (2005).

    CAS  Google Scholar 

  77. He, L. F., Hou, S. K., Yan, Z., Ren, L. & Wang, S. W. [The heat shock protein 70 antisense oligomers enhance the sensitivity of bladder cancer cell EJ to mitomycin C]. Zhonghua Wai Ke Za Zhi 42, 1108–1110 (2004).

    PubMed  Google Scholar 

  78. Kamal, A. A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors. Nature 425, 407–410 (2003).

    Article  CAS  PubMed  Google Scholar 

  79. Karkoulis, P. K., Stravopodis, D. J., Margaritis, L. H. & Voutsinas, G. E. 17-Allylamino-17-demethoxygeldanamycin induces downregulation of critical Hsp90 protein clients and results in cell cycle arrest and apoptosis of human urinary bladder cancer cells. BMC Cancer 10, 481 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Yoshida, S. Low-dose Hsp90 inhibitors tumor-selectively sensitize bladder cancer cells to chemoradiotherapy. Cell Cycle 10, 4291–4299 (2011).

    Article  CAS  PubMed  Google Scholar 

  81. Tatokoro, M. Potential role of Hsp90 inhibitors in overcoming cisplatin resistance of bladder cancer-initiating cells. Int. J. Cancer 131, 987–996 (2012).

    Article  CAS  PubMed  Google Scholar 

  82. Colombo, R. Combination of intravesical chemotherapy and hyperthermia for the treatment of superficial bladder cancer: preliminary clinical experience. Crit. Rev. Oncol. Hematol. 47, 127–139 (2003).

    Article  CAS  PubMed  Google Scholar 

  83. Carver, J. A., Rekas, A., Thorn, D. C. & Wilson, M. R. Small heat-shock proteins and clusterin: intra- and extracellular molecular chaperones with a common mechanism of action and function? IUBMB Life 55, 661–668 (2003).

    Article  CAS  PubMed  Google Scholar 

  84. Gleave, M., Miyake, H., Zangemeister-Wittke, U. & Jansen, B. Antisense therapy: current status in prostate cancer and other malignancies. Cancer Metastasis Rev. 21, 79–92 (2002).

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  86. 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 

  87. 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).

    Google Scholar 

  88. 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 

  89. Shiota, M. 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 

  90. Chi, K. N. 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 

  91. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  92. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  93. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  94. Ekici, S., Eroglu, A., Dogan Ekici, A. I. & Turkeri, L. Clusterin immunoreactivity as a predictive factor for progression of non-muscle-invasive bladder carcinoma. Urol. Int. 86, 31–35 (2011).

    Article  PubMed  Google Scholar 

  95. Muramaki, M. Chemosensitization of gemcitabine-resistant human bladder cancer cell line both in vitro and in vivo using antisense oligonucleotide targeting the anti-apoptotic gene, clusterin. BJU Int. 103, 384–390 (2009).

    Article  CAS  PubMed  Google Scholar 

  96. Chung, J. Enhanced chemosensitivity of bladder cancer cells to cisplatin by suppression of clusterin in vitro. Cancer Lett. 203, 155–161 (2004).

    Article  CAS  PubMed  Google Scholar 

  97. Miyake, H., Hara, I., Kamidono, S. & Gleave, M. E. Synergistic chemsensitization and inhibition of tumor growth and metastasis by the antisense oligodeoxynucleotide targeting clusterin gene in a human bladder cancer model. Clin. Cancer Res. 7, 4245–4252 (2001).

    CAS  PubMed  Google Scholar 

  98. Yamanaka, K., Gleave, M., Muramaki, M., Hara, I. & Miyake, H. Enhanced radiosensitivity by inhibition of the anti-apoptotic gene clusterin using antisense oligodeoxynucleotide in a human bladder cancer model. Oncol. Rep. 13, 885–890 (2005).

    CAS  PubMed  Google Scholar 

  99. Lu, J. Lentivirus-mediated RNA interference of clusterin enhances the chemosensitivity of EJ bladder cancer cells to epirubicin in vitro. Mol. Med. Report 6, 1133–1139 (2012).

    Article  CAS  Google Scholar 

  100. Miyake, H. et al. Synergistic antitumor activity by combined treatment with gemcitabine and antisense oligodeoxynucleotide targeting clusterin gene in an intravesical administration model against human bladder cancer kotcc-1 cells. J. Urol. 171, 2477–2481 (2004).

    Article  CAS  PubMed  Google Scholar 

  101. Li, H. Identification of Apo-A1 as a biomarker for early diagnosis of bladder transitional cell carcinoma. Proteome Sci. 9, 21 (2001).

    Article  CAS  Google Scholar 

  102. Hazzaa, S. M., Elashry, O. M. & Afifi, I. K. Clusterin as a diagnostic and prognostic marker for transitional cell carcinoma of the bladder. Pathol. Oncol. Res. 16, 101–109 (2010).

    Article  CAS  PubMed  Google Scholar 

  103. Miyake, H., Gleave, M., Kamidono, S. & Hara, I. Overexpression of clusterin in transitional cell carcinoma of the bladder is related to disease progression and recurrence. Urology 59, 150–154 (2002).

    Article  PubMed  Google Scholar 

  104. Orenes-Pinero, E. Serum and tissue profiling in bladder cancer combining protein and tissue arrays. J. Proteome Res. 9, 164–173 (2010).

    Article  CAS  PubMed  Google Scholar 

  105. US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  106. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

Download references

Author information

Authors and Affiliations

  1. Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia, 2660 Oak Street, Vancouver, V6H 3Z6, BC, Canada

    Joseph Ischia & Alan I. So

Authors
  1. Joseph Ischia
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alan I. So
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

J. Ischia researched the literature for this Review article. Both authors then wrote, edited, reviewed, and discussed the content of the article.

Corresponding author

Correspondence to Alan I. So.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ischia, J., So, A. The role of heat shock proteins in bladder cancer. Nat Rev Urol 10, 386–395 (2013). https://doi.org/10.1038/nrurol.2013.108

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrurol.2013.108

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer