This Article Full Text Full Text (PDF) Supplementary Data 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 Sharma, A. Articles by Knudsen, K. E. Search for Related Content PubMed PubMed Citation Articles by Sharma, A. Articles by Knudsen, K. E.

Retinoblastoma Tumor Suppressor Status Is a Critical Determinant of Therapeutic Response in Prostate Cancer Cells

Departments of ¹ Cell and Cancer Biology and ² Psychiatry, ³ Center for Environmental Genetics, ⁴ Barrett Cancer Center, and ⁵ Department of Biomedical Engineering, University of Cincinnati College of Medicine, Cincinnati, Ohio

Requests for reprints: Karen E. Knudsen, Department of Cell and Cancer Biology, 3125 Eden Avenue, ML 0521, Vontz Center for Molecular Studies, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0521. Phone: 513-558-7371; Fax: 513-558-4454; E-mail: Karen.Knudsen{at}uc.edu.

The retinoblastoma tumor suppressor protein (RB), a critical mediator of cell cycle progression, is functionally inactivated in the majority of human cancers, including prostatic adenocarcinoma. The importance of RB tumor suppressor function in this disease is evident because 25% to 50% of prostatic adenocarcinomas harbor aberrations in RB pathway. However, no previous studies challenged the consequence of RB inactivation on tumor cell proliferation or therapeutic response. Here, we show that RB depletion facilitates deregulation of specific E2F target genes, but does not confer a significant proliferative advantage in the presence of androgen. However, RB-deficient cells failed to elicit a cytostatic response (compared with RB proficient isogenic controls) when challenged with androgen ablation, AR antagonist, or combined androgen blockade. These data indicate that RB deficiency can facilitate bypass of first-line hormonal therapies used to treat prostate cancer. Given the established effect of RB on DNA damage checkpoints, these studies were then extended to determine the impact of RB depletion on the response to cytotoxic agents used to treat advanced disease. In this context, RB-deficient prostate cancer cells showed enhanced susceptibility to cell death induced by only a selected subset of cytotoxic agents (antimicrotubule agents and a topoisomerase inhibitor). Combined, these data indicate that RB depletion dramatically alters the cellular response to therapeutic intervention in prostate cancer cells and suggest that RB status could potentially be developed as a marker for effectively directing therapy. [Cancer Res 2007;67(13):6192–203]

This article has been cited by other articles:

				M. Popowski, H. A. Ferguson, A. M. Sion, E. Koller, E. Knudsen, and C. L. Van Den Berg Stress and IGF-I Differentially Control Cell Fate through Mammalian Target of Rapamycin (mTOR) and Retinoblastoma Protein (pRB) J. Biol. Chem., October 17, 2008; 283(42): 28265 - 28273. [Abstract] [Full Text] [PDF]

				S. Shah, J. K. Hess-Wilson, S. Webb, H. Daly, S. Godoy-Tundidor, J. Kim, J. Boldison, Y. Daaka, and K. E. Knudsen 2,2-Bis(4-Chlorophenyl)-1,1-Dichloroethylene Stimulates Androgen Independence in Prostate Cancer Cells through Combinatorial Activation of Mutant Androgen Receptor and Mitogen-Activated Protein Kinase Pathways Mol. Cancer Res., September 1, 2008; 6(9): 1507 - 1520. [Abstract] [Full Text] [PDF]