Advertisement

Heat Shock Proteins and Cancer

  • Ganachari M. Nagaraja
  • Alexzander AseaEmail author
Chapter
Part of the Heat Shock Proteins book series (HESP, volume 5)

Abstract

Heat shock proteins (HSP) play multiple roles in cellular physiology and pathology depending on a wide variety of factors including its relative location within the cell (intracellular, plasma membrane or extracellular milieu), the age of the cell or whether it has undergone neoplastic transformation. In normal non-transformed cells, HSP play a cytoprotective role and protect cells from adverse stressful stimuli via chaperoning naïve, misfolded and/or denatured proteins by a process known as the stress response. However, cancer cells have commandeered this function and the result is increased resistance to a number of anti-cancer therapies including hyperthermia, radiation and a wide range of chemotherapeutic agents. Recent advances in our understanding of this dual role of HSP have led to the development of pharmacological and molecular tool to target HSP for therapeutic gain. In this chapter, we highlight evidence for the involvement of HSP in the pathology of various cancers and discuss their proposed mechanism of action and therapeutic potential

Keywords

Apoptosis cancer cytotoxicity heat shock proteins tumors 

Abbreviations

AP-1

activator protein-1

AR

androgen receptor

CRC

colorectal cancer

CTL

cytotoxic T lymphocytes

ERK

extracellular-signal regulated kinase

GRP

glucose regulated proteins

HBV

hepatitis B virus

HCC

hepatocellular carcinoma cells

HCV

hepatitis C virus

HER

human endothelial growth factor receptor

HSF

heat shock factor

Hsp

heat shock proteins

hsp

heat shock protein gene

HSP

heat shock protein family

HSP

heat shock protein family gene

JAK/STAT

janus-activated-kinase/signal transducer and activator of transcription

MAPK

mitogen activated protein kinase

NK cells

natural killer cells

NSCLC

non-small cell lung cancer

PSA

prostate specific antigen

SAPK/JNK

stress-activated protein kinase/c-Jun N-terminal kinase

SCC

squamous cell carcinoma

SCLC

small cell lung cancer

Notes

Acknowledgements

This work was supported in part by a grant from the Scott & White Memorial Hospital and Clinic (to G. M. N.), the National Institutes of Health grant RO1CA91889, institutional support from Scott & White Memorial Hospital and Clinic, Texas A&M University System Health Science Center College of Medicine, the Central Texas Veterans Health Administration and an Endowment from the Cain Foundation (to A. A.).

References

  1. Abe, M., Manola, J. B., Oh, W. K., Parslow, D. L., George, D. J., Austin, C. L. and Kantoff, P. W. (2004) Plasma levels of heat shock protein 70 in patients with prostate cancer: a potential biomarker for prostate cancer. Clin Prostate Cancer 3, 49–53.PubMedGoogle Scholar
  2. Barnes, J. A., Dix, D. J., Collins, B. W., Luft, C. and Allen, J. W. (2001) Expression of inducible Hsp70 enhances the proliferation of MCF-7 breast cancer cells and protects against the cytotoxic effects of hyperthermia. Cell Stress Chaperones 6, 316–25.CrossRefPubMedGoogle Scholar
  3. Bausero, M. A., Bharti, A., Page, D. T., Perez, K. D., Eng, J. W., Ordonez, S. L., Asea, E. E., Jantschitsch, C., Kindas-Muegge, I., Ciocca, D. and Asea, A. (2005) Silencing the hsp25 gene eliminates migration capability of the highly metastatic murine 4T1 breast adenocarcinoma cell. Tumour Biol 27, 17–26.CrossRefPubMedGoogle Scholar
  4. Bausero, M. A., Page, D. T., Osinaga, E. and Asea, A. (2004) Surface expression of Hsp25 and Hsp72 differentially regulates tumor growth and metastasis. Tumour Biol 25, 243–51.CrossRefPubMedGoogle Scholar
  5. Bonay, M., Soler, P., Riquet, M., Battesti, J. P., Hance, A. J. and Tazi, A. (1994) Expression of heat shock proteins in human lung and lung cancers. Am J Respir Cell Mol Biol 10, 453–61.PubMedGoogle Scholar
  6. Brizel, D. M., Scully, S. P., Harrelson, J. M., Layfield, L. J., Bean, J. M., Prosnitz, L. R. and Dewhirst, M. W. (1996) Tumor oxygenation predicts for the likelihood of distant metastases in human soft tissue sarcoma. Cancer Res 56, 941–3.PubMedGoogle Scholar
  7. Calderwood, S. K., Khaleque, M. A., Sawyer, D. B. and Ciocca, D. R. (2006) Heat shock proteins in cancer: chaperones of tumorigenesis. Trends Biochem Sci 31, 164–72.CrossRefPubMedGoogle Scholar
  8. Cappello, F., Bellafiore, M., David, S., Anzalone, R. and Zummo, G. (2003a) Ten kilodalton heat shock protein (HSP10) is overexpressed during carcinogenesis of large bowel and uterine exocervix. Cancer Lett 196, 35–41.CrossRefPubMedGoogle Scholar
  9. Cappello, F., Bellafiore, M., Palma, A., David, S., Marciano, V., Bartolotta, T., Sciume, C., Modica, G., Farina, F., Zummo, G. and Bucchieri, F. (2003b) 60 KDa chaperonin (HSP60) is over-expressed during colorectal carcinogenesis. Eur J Histochem 47, 105–10.PubMedGoogle Scholar
  10. Cappello, F., Rappa, F., David, S., Anzalone, R. and Zummo, G. (2003c) Immunohistochemical evaluation of PCNA, p53, HSP60, HSP10 and MUC-2 presence and expression in prostate carcinogenesis. Anticancer Res 23, 1325–31.PubMedGoogle Scholar
  11. Chuma, M., Sakamoto, M., Yamazaki, K., Ohta, T., Ohki, M., Asaka, M. and Hirohashi, S. (2003) Expression profiling in multistage hepatocarcinogenesis: identification of HSP70 as a molecular marker of early hepatocellular carcinoma. Hepatology 37, 198–207.CrossRefPubMedGoogle Scholar
  12. Ciocca, D. R. and Calderwood, S. K. (2005) Heat shock proteins in cancer: diagnostic, prognostic, predictive, and treatment implications. Cell Stress Chaperones 10, 86–103.CrossRefPubMedGoogle Scholar
  13. Ciocca, D. R., Oesterreich, S., Chamness, G. C., McGuire, W. L. and Fuqua, S. A. (1993) Biological and clinical implications of heat shock protein 27,000 (Hsp27): a review. J Natl Cancer Inst 85, 1558–70.CrossRefPubMedGoogle Scholar
  14. Cleator, S. and Ashworth, A. (2004) Molecular profiling of breast cancer: clinical implications. Br J Cancer 90, 1120–4.CrossRefPubMedGoogle Scholar
  15. Cornford, P. A., Dodson, A. R., Parsons, K. F., Desmond, A. D., Woolfenden, A., Fordham, M., Neoptolemos, J. P., Ke, Y. and Foster, C. S. (2000) Heat shock protein expression independently predicts clinical outcome in prostate cancer. Cancer Res 60, 7099–105.PubMedGoogle Scholar
  16. Craft, N., Shostak, Y., Carey, M. and Sawyers, C. L. (1999) A mechanism for hormone-independent prostate cancer through modulation of androgen receptor signaling by the HER-2/neu tyrosine kinase. Nat Med 5, 280–5.CrossRefPubMedGoogle Scholar
  17. Cullinan, S. B. and Whitesell, L. (2006) Heat shock protein 90: a unique chemotherapeutic target. Semin Oncol 33, 457–65.CrossRefPubMedGoogle Scholar
  18. Diehl, J. A., Yang, W., Rimerman, R. A., Xiao, H. and Emili, A. (2003) Hsc70 regulates accumulation of cyclin D1 and cyclin D1-dependent protein kinase. Mol Cell Biol 23, 1764–74.CrossRefPubMedGoogle Scholar
  19. Ellis, R. J. and van der Vies, S. M. (1991) Molecular chaperones. Annu Rev Biochem 60, 321–47.CrossRefPubMedGoogle Scholar
  20. Eustace, B. K., Sakurai, T., Stewart, J. K., Yimlamai, D., Unger, C., Zehetmeier, C., Lain, B., Torella, C., Henning, S. W., Beste, G., Scroggins, B. T., Neckers, L., Ilag, L. L. and Jay, D. G. (2004) Functional proteomic screens reveal an essential extracellular role for hsp90 alpha in cancer cell invasiveness. Nat Cell Biol 6, 507–14.CrossRefPubMedGoogle Scholar
  21. Fidler, I. J. (1990) Critical factors in the biology of human cancer metastasis: twenty-eighth G.H.A. Clowes memorial award lecture. Cancer Res 50, 6130–8.PubMedGoogle Scholar
  22. Georgopoulos, C. and Welch, W. J. (1993) Role of the major heat shock proteins as molecular chaperones. Annu Rev Cell Biol 9, 601–34.CrossRefPubMedGoogle Scholar
  23. Gimenez-Bonafe, P., Fedoruk, M. N., Whitmore, T. G., Akbari, M., Ralph, J. L., Ettinger, S., Gleave, M. E. and Nelson, C. C. (2004) YB-1 is upregulated during prostate cancer tumor progression and increases P-glycoprotein activity. Prostate 59, 337–49.CrossRefPubMedGoogle Scholar
  24. Hanahan, D. and Weinberg, R. A. (2000) The hallmarks of cancer. Cell 100, 57–70.CrossRefPubMedGoogle Scholar
  25. Hantschel, M., Pfister, K., Jordan, A., Scholz, R., Andreesen, R., Schmitz, G., Schmetzer, H., Hiddemann, W. and Multhoff, G. (2000) Hsp70 plasma membrane expression on primary tumor biopsy material and bone marrow of leukemic patients. Cell Stress Chaperones 5, 438–42.CrossRefPubMedGoogle Scholar
  26. Hurwitz, M. D., Kaur, P., Zheng, H., Nagaraja, G. M., Bausero, M. A., Asea, A. (2009) Radiotherapy-induced tumor-derived HSP modulates immune responses of patients with prostate cancer (in preparation).Google Scholar
  27. Hwang, T. S., Han, H. S., Choi, H. K., Lee, Y. J., Kim, Y. J., Han, M. Y. and Park, Y. M. (2003) Differential, stage-dependent expression of Hsp70, Hsp110 and Bcl-2 in colorectal cancer. J Gastroenterol Hepatol 18, 690–700.CrossRefPubMedGoogle Scholar
  28. Jaattela, M. (1999) Escaping cell death: survival proteins in cancer. Exp Cell Res 248, 30–43.CrossRefPubMedGoogle Scholar
  29. Jackson, R. M. and Garcia-Rojas, R. (2008) Kinase activity, heat shock protein 27 phosphorylation, and lung epithelial cell glutathione. Exp Lung Res 34, 245–62.CrossRefPubMedGoogle Scholar
  30. Jemal, A., Siegel, R., Ward, E., Murray, T., Xu, J., Smigal, C. and Thun, M. J. (2006) Cancer statistics, 2006. CA Cancer J Clin 56, 106–30.CrossRefPubMedGoogle Scholar
  31. Joo, M., Chi, J. G. and Lee, H. (2005) Expressions of HSP70 and HSP27 in hepatocellular carcinoma. J Korean Med Sci 20, 829–34.CrossRefPubMedGoogle Scholar
  32. Kalogeraki, A., Giannikaki, E., Tzardi, M., Kafousi, M., Ieromonachou, P., Dariviannaki, K., Askoxylakis, J., Tsiftsis, D., Stathopoulos, E. and Zoras, O. (2007) Correlation of heat shock protein (HSP70) expression with cell proliferation (MIB1), estrogen receptors (ER) and clinicopathological variables in invasive ductal breast carcinomas. J Exp Clin Cancer Res 26, 367–8.PubMedGoogle Scholar
  33. King, K. L., Li, A. F., Chau, G. Y., Chi, C. W., Wu, C. W., Huang, C. L. and Lui, W. Y. (2000) Prognostic significance of heat shock protein-27 expression in hepatocellular carcinoma and its relation to histologic grading and survival. Cancer 88, 2464–70.CrossRefPubMedGoogle Scholar
  34. Kurup, A. and Hanna, N. H. (2004) Treatment of small cell lung cancer. Crit Rev Oncol Hematol 52, 117–26.CrossRefPubMedGoogle Scholar
  35. Lindquist, S. (1986) The heat-shock response. Annu Rev Biochem 55, 1151–91.CrossRefPubMedGoogle Scholar
  36. Lindquist, S. and Craig, E. A. (1988) The heat-shock proteins. Annu Rev Genet 22, 631–77.CrossRefPubMedGoogle Scholar
  37. Malusecka, E., Zborek, A., Krzyzowska-Gruca, S. and Krawczyk, Z. (2001) Expression of heat shock proteins HSP70 and HSP27 in primary non-small cell lung carcinomas. An immunohistochemical study. Anticancer Res 21, 1015–21.PubMedGoogle Scholar
  38. Matsushima-Nishiwaki, R., Takai, S., Adachi, S., Minamitani, C., Yasuda, E., Noda, T., Kato, K., Toyoda, H., Kaneoka, Y., Yamaguchi, A., Kumada, T. and Kozawa, O. (2008) Phosphorylated heat shock protein 27 represses growth of hepatocellular carcinoma via inhibition of extracellular signal-regulated kinase. J Biol Chem 283, 18852–60.CrossRefPubMedGoogle Scholar
  39. Mosser, D. D. and Morimoto, R. I. (2004) Molecular chaperones and the stress of oncogenesis. Oncogene 23, 2907–18.CrossRefPubMedGoogle Scholar
  40. Multhoff, G., Botzler, C., Wiesnet, M., Muller, E., Meier, T., Wilmanns, W. and Issels, R. D. (1995) A stress-inducible 72-kDa heat-shock protein (HSP72) is expressed on the surface of human tumor cells, but not on normal cells. Int J Cancer 61, 272–9.CrossRefPubMedGoogle Scholar
  41. Nagaraja, G. M., Zheng, H., Kaur, P., Neumann, W., Bausero, M. A., Asea, E. E., Multhoff, G. and Asea, A. (2009) Silencing Hsp25 using lentivirus-RNAi inhibits tumor growth and metastasis by augmenting CD8+ CTL activity (in preparation).Google Scholar
  42. Neckers, L. (2007) Heat shock protein 90: the cancer chaperone. J Biosci 32, 517–30.CrossRefPubMedGoogle Scholar
  43. Nylandsted, J., Brand, K. and Jaattela, M. (2000) Heat shock protein 70 is required for the survival of cancer cells. Ann N Y Acad Sci 926, 122–5.CrossRefPubMedGoogle Scholar
  44. Perotti, C., Liu, R., Parusel, C. T., Bocher, N., Schultz, J., Bork, P., Pfitzner, E., Groner, B. and Shemanko, C. S. (2008) Heat shock protein-90-alpha, a prolactin-STAT5 target gene identified in breast cancer cells, is involved in apoptosis regulation. Breast Cancer Res 10, R94.CrossRefPubMedGoogle Scholar
  45. Pick, E., Kluger, Y., Giltnane, J. M., Moeder, C., Camp, R. L., Rimm, D. L. and Kluger, H. M. (2007) High HSP90 expression is associated with decreased survival in breast cancer. Cancer Res 67, 2932–7.CrossRefPubMedGoogle Scholar
  46. Pratt, W. B., Galigniana, M. D., Morishima, Y. and Murphy, P. J. (2004) Role of molecular chaperones in steroid receptor action. Essays Biochem 40, 41–58.PubMedGoogle Scholar
  47. Prescott, J. and Coetzee, G. A. (2006) Molecular chaperones throughout the life cycle of the androgen receptor. Cancer Lett 231, 12–9.CrossRefPubMedGoogle Scholar
  48. Queitsch, C., Sangster, T. A. and Lindquist, S. (2002) Hsp90 as a capacitor of phenotypic variation. Nature 417, 618–24.CrossRefPubMedGoogle Scholar
  49. Ritossa, F. (1996) Discovery of the heat shock response. Cell Stress Chaperones 1, 97–8.CrossRefPubMedGoogle Scholar
  50. Rodina, A., Vilenchik, M., Moulick, K., Aguirre, J., Kim, J., Chiang, A., Litz, J., Clement, C. C., Kang, Y., She, Y., Wu, N., Felts, S., Wipf, P., Massague, J., Jiang, X., Brodsky, J. L., Krystal, G. W. and Chiosis, G. (2007) Selective compounds define Hsp90 as a major inhibitor of apoptosis in small-cell lung cancer. Nat Chem Biol 3, 498–507.CrossRefPubMedGoogle Scholar
  51. Sherwood, E. R., Van Dongen, J. L., Wood, C. G., Liao, S., Kozlowski, J. M. and Lee, C. (1998) Epidermal growth factor receptor activation in androgen-independent but not androgen-stimulated growth of human prostatic carcinoma cells. Br J Cancer 77, 855–61.PubMedGoogle Scholar
  52. Sorger, P. K. and Pelham, H. R. (1988) Yeast heat shock factor is an essential DNA-binding protein that exhibits temperature-dependent phosphorylation. Cell 54, 855–64.CrossRefPubMedGoogle Scholar
  53. Storm, F. K., Gilchrist, K. W., Warner, T. F. and Mahvi, D. M. (1995) Distribution of Hsp-27 and HER-2/neu in in situ and invasive ductal breast carcinomas. Ann Surg Oncol 2, 43–8.CrossRefPubMedGoogle Scholar
  54. Storm, F. K., Mahvi, D. M. and Gilchrist, K. W. (1996) Heat shock protein 27 overexpression in breast cancer lymph node metastasis. Ann Surg Oncol 3, 570–3.CrossRefPubMedGoogle Scholar
  55. Sun, W., Xing, B., Sun, Y., Du, X., Lu, M., Hao, C., Lu, Z., Mi, W., Wu, S., Wei, H., Gao, X., Zhu, Y., Jiang, Y., Qian, X. and He, F. (2007) Proteome analysis of hepatocellular carcinoma by two-dimensional difference gel electrophoresis: novel protein markers in hepatocellular carcinoma tissues. Mol Cell Proteomics 6, 1798–808.CrossRefPubMedGoogle Scholar
  56. Takashima, M., Kuramitsu, Y., Yokoyama, Y., Iizuka, N., Toda, T., Sakaida, I., Okita, K., Oka, M. and Nakamura, K. (2003) Proteomic profiling of heat shock protein 70 family members as biomarkers for hepatitis C virus-related hepatocellular carcinoma. Proteomics 3, 2487–93.CrossRefPubMedGoogle Scholar
  57. Teng, S. C., Chen, Y. Y., Su, Y. N., Chou, P. C., Chiang, Y. C., Tseng, S. F. and Wu, K. J. (2004) Direct activation of HSP90A transcription by c-Myc contributes to c-Myc-induced transformation. J Biol Chem 279, 14649–55.CrossRefPubMedGoogle Scholar
  58. Vaupel, P., Kallinowski, F. and Okunieff, P. (1989) Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. Cancer Res 49, 6449–65.PubMedGoogle Scholar
  59. Veronesi, U., Boyle, P., Goldhirsch, A., Orecchia, R. and Viale, G. (2005) Breast cancer. Lancet 365, 1727–41.CrossRefPubMedGoogle Scholar
  60. Volm, M., Koomagi, R., Mattern, J. and Stammler, G. (1995) Heat shock (hsp70) and resistance proteins in non-small cell lung carcinomas. Cancer Lett 95, 195–200.CrossRefPubMedGoogle Scholar
  61. Wang, Q., An, L., Chen, Y. and Yue, S. (2002) Expression of endoplasmic reticulum molecular chaperon GRP94 in human lung cancer tissues and its clinical significance. Chin Med J (Engl) 115, 1615–9.Google Scholar
  62. Welch, W. J. (1992) Mammalian stress response: cell physiology, structure/function of stress proteins, and implications for medicine and disease. Physiol Rev 72, 1063–81.PubMedGoogle Scholar
  63. Yano, M., Naito, Z., Yokoyama, M., Shiraki, Y., Ishiwata, T., Inokuchi, M. and Asano, G. (1999) Expression of hsp90 and cyclin D1 in human breast cancer. Cancer Lett 137, 45–51.CrossRefPubMedGoogle Scholar
  64. Yao, D. F., Wu, X. H., Su, X. Q., Yao, M., Wu, W., Qiu, L. W., Zou, L. and Meng, X. Y. (2006) Abnormal expression of HSP gp96 associated with HBV replication in human hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int 5, 381–6.PubMedGoogle Scholar
  65. Zakowski, M. F. (2003) Pathology of small cell carcinoma of the lung. Semin Oncol 30, 3–8.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  1. 1.Division of Investigative PathologyThe Texas A&M Health Science Center College of Medicine, Scott & White Memorial Hospital and ClinicTempleUSA
  2. 2.Division of Investigative Pathology, The Texas A&M Health Science Center College of MedicineScott & White Memorial Hospital and ClinicTempleUSA

Personalised recommendations