BERKELEY, CA (UroToday.com) - The androgen receptor is the principal target for treatment in patients with non-organ confined prostate cancer. First-line androgen deprivation therapy interferes with systemic production of androgens and/or consists of administration of antiandrogens that prevent androgens from binding to and thereby activating androgen receptor.
Androgen deprivation therapy initially results in remission but eventually fails and gives rise to castration-recurrent prostate cancer. Nonetheless, androgen receptor action remains essential for proliferation of castration-recurrent prostate cancer cells. Novel, second-line androgen deprivation approaches that inhibit intracrine androgen biosynthesis or involve administration of more potent, second-generation antiandrogens demonstrate antitumor activity and survival benefits in castration-recurrent prostate cancer patients, but are not curative. Androgen receptor-dependent mechanisms similar to those that underlie reemergence of prostate cancer during initial androgen deprivation are responsible for disease recurrence during second generation androgen deprivation, and the resulting disease is sensitive to further manipulation of the androgen receptor signaling axis.
| "These findings underscore the potential of the RhoA signaling axis..." |
While initially successful, androgen deprivation therapies eventually fail despite continued reliance of prostate cancer cells on androgen receptor activity. Failure of androgen deprivation therapy accounts for the vast majority of prostate cancer-related mortality, estimated at 28,170 deaths in the United States in 2012, and indicates that critical aspects of androgen receptor action that drive prostate cancer progression are not inhibited. In addition, due to extra-prostatic actions that affect the cardiovascular, musculoskeletal, and central nervous systems, androgen deprivation therapy is associated with significant side effects that impact negatively the quality of life of the more than 600,000 prostate cancer patients who are currently on androgen deprivation in the United States, and, particularly in the case of second-line androgen deprivation therapy, necessitate additional pharmacological intervention. The development of more effective and selective methods to target androgen receptor activity for prostate cancer therapy hinges on the identification of clinically relevant androgen-dependent events that drive prostate cancer progression and insights into the molecular mechanisms by which androgens control these events.
Recently we identified a novel mechanism of androgen action that is dependent on the transcription factor serum response factor (SRF). The SRF-dependent mechanism of androgen action conveys androgen-responsiveness to a subset (less than 6 percent) of androgen-dependent genes in prostate cancer cells, separates benign from malignant prostate samples, correlates with aggressive disease and poor outcome, and is enriched in prostate cancer. This expression profile represents the first distinct mechanism of androgen action with clinical relevance in prostate cancer and provides the rationale to develop novel and more effective forms of androgen deprivation. Here, investigation of the mechanism by which androgens regulate SRF activity determined that the small GTPase RhoA mediates androgen-responsiveness of more than half of SRF target genes. Androgen treatment induced RhoA activation. In clinical specimens RhoA expression was higher in prostate cancer cells than benign prostate cells, and elevated RhoA expression levels were associated with aggressive disease features and decreased disease-free survival following radical prostatectomy. Androgen-responsiveness of SRF target genes continued to rely on androgen receptor, RhoA, and SRF in model systems that mimic the progression from androgen-stimulated to castration-recurrent prostate cancer. These findings underscore the potential of the RhoA signaling axis, which harbors drugable targets, as a novel therapeutic target to block selectively a signaling pathway downstream of androgen receptor that controls the expression of genes that drive prostate cancer progression.
Written by:
Hannelore V. Heemers, PhD* as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
*Assistant Professor
Department of Urology
Roswell Park Cancer Institute
Cell and Virus Annex, Rooms 142-144
Elm & Carlton Streets
Buffalo, NY 14263
E-mail :
RhoA as a mediator of clinically relevant androgen action in prostate cancer cells - Abstract
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