This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pootrakul, L. Articles by Cote, R. J. Search for Related Content PubMed PubMed Citation Articles by Pootrakul, L. Articles by Cote, R. J.

Expression of Stress Response Protein Grp78 Is Associated with the Development of Castration-Resistant Prostate Cancer

Authors' Affiliations: ¹ Department of Pathology, University of Southern California, Keck School of Medicine/USC Norris Comprehensive Cancer Center; Departments of ² Preventive Medicine, ³ Biochemistry, and ⁴ Urology, University of Southern California, Los Angeles, California

Requests for reprints: Richard J. Cote, University of Southern California/Norris Comprehensive Cancer Center, 1441 Eastlake Avenue NOR 2424, Los Angeles, CA 90033. Phone: 323-865-0212; Fax: 323-865-0077; E-mail: cote_r{at}ccnt.hsc.usc.edu.

Background: Induction of molecular chaperone Grp78 (78-kDa glucose-regulated protein) occurs in stress conditions that often characterize tumor microenvironments. We investigated the role of Grp78 in prostate cancer progression and the development of castration resistance, where cancer cells continue to survive despite the stress of an androgen-starved environment.

Experimental Design: Immunohistochemistry was done to examine Grp78 expression in 219 prostate cancers from patients with pathologic stage T₃N₀M₀ disease [androgen ablation naive (untreated) and androgen ablation exposed (treated)] and castration-resistant prostate cancer. Classification of tumors was based on intensity of Grp78 cytoplasmic immunoreactivity and percentage of immunoreactive tumor cells. The associations of Grp78 expression with prostate cancer recurrence (clinical and/or serum prostate-specific antigen) and survival were examined in the untreated stage T₃N₀M₀ group. Grp78 expression was also analyzed in the androgen-dependent LNCaP and castration-resistant C42B cell lines.

Results: The percentage of tumor cells expressing Grp78 was strongly associated with castration-resistant status (P = 0.005). Increased Grp78 expression was consistently associated with greater risk of prostate cancer recurrence and worse overall survival in patients who had not undergone prior hormonal manipulation. Grp78 expression was also increased in the castration-resistant LNCaP-derived cell line C42B and in LNCaP cells grown in androgen-deprived conditions compared with LNCaP cells grown in androgen-rich media.

Conclusion: Our findings show that up-regulation of Grp78 is associated with the development of castration resistance, possibly in part by augmenting cell survival as previously suggested, and may serve as an important prognostic indicator of recurrence in a subset of patients with T₃N₀M₀ disease.

This article has been cited by other articles:

				Y. Tang, L. Wang, O. Goloubeva, M. Afnan Khan, B. Zhang, and A. Hussain Divergent Effects of Castration on Prostate Cancer in TRAMP Mice: Possible Implications for Therapy Clin. Cancer Res., May 15, 2008; 14(10): 2936 - 2943. [Abstract] [Full Text] [PDF]

				D. Dong, M. Ni, J. Li, S. Xiong, W. Ye, J. J. Virrey, C. Mao, R. Ye, M. Wang, L. Pen, et al. Critical Role of the Stress Chaperone GRP78/BiP in Tumor Proliferation, Survival, and Tumor Angiogenesis in Transgene-Induced Mammary Tumor Development Cancer Res., January 15, 2008; 68(2): 498 - 505. [Abstract] [Full Text] [PDF]

				C. C. Jiang, L. H. Chen, S. Gillespie, Y. F. Wang, K. A. Kiejda, X. D. Zhang, and P. Hersey Inhibition of MEK Sensitizes Human Melanoma Cells to Endoplasmic Reticulum Stress-Induced Apoptosis Cancer Res., October 15, 2007; 67(20): 9750 - 9761. [Abstract] [Full Text] [PDF]

				C. G. Jakobsen, N. Rasmussen, A.-V. Laenkholm, and H. J. Ditzel Phage Display Derived Human Monoclonal Antibodies Isolated by Binding to the Surface of Live Primary Breast Cancer Cells Recognize GRP78 Cancer Res., October 1, 2007; 67(19): 9507 - 9517. [Abstract] [Full Text] [PDF]

				G. BANHEGYI, P. BAUMEISTER, A. BENEDETTI, D. DONG, Y. FU, A. S. LEE, J. LI, C. MAO, E. MARGITTAI, M. NI, et al. Endoplasmic Reticulum Stress Ann. N.Y. Acad. Sci., October 1, 2007; 1113(1): 58 - 71. [Abstract] [Full Text] [PDF]

				A. S. Lee GRP78 Induction in Cancer: Therapeutic and Prognostic Implications Cancer Res., April 15, 2007; 67(8): 3496 - 3499. [Abstract] [Full Text] [PDF]