Posted January 16, 2014
Yaping Tu, Ph.D., Creighton University School of Medicine
Androgen ablation therapy, which limits production of the male sex hormone androgen and/or blocks androgen receptors to suppress prostate cancer cell growth, is the major treatment for advanced prostate cancer, but often leads to development of a lethal, hormone-resistant form of cancer. To combat this issue, many researchers are trying to understand the mechanism behind hormone-resistance, which could lead to the development of more effective treatments.
Dr. Yaping Tu and his team at Creighton University have been studying the activation of G-protein coupled receptors (GPCR) on the prostate cancer cell surface, which, when activated by hormones, can cause abnormal activation of androgen receptors during hormone therapy (Figure 1). Drugs inhibiting individual GPCR function are already widely used in treating various human diseases. However, there are many different GPCRs and redundancies in GPCR activation in cancer can offset the desired effects of blocking any single GPCR type. Dr. Tu's group has used support from an FY06 PCRP Idea Development Award to identify a regulator of GPCR functions, called RGS2 (Regulator of G-Protein Signaling 2), that provides a new option for targeting the GPCR pathway. Animal and cell line experiments showed that blocking the activity of RGS2 stimulated prostate cancer cell growth independent of androgens, and also made the cells more sensitive to lower levels of androgens, potentially making these cells more prone to survival during hormone therapy.
This discovery makes RGS2 an attractive therapeutic target, since one RGS2 molecule could inhibit responses from multiple types of GPCRs and ultimately provide an effective strategy for suppressing activation of androgen-insensitive androgen receptors. Dr. Tu and his group are now translating these findings to a larger study by investigating if lowered RGS2 levels in prostate tissues correlate with poor patient outcomes. Their findings to date suggest that the RGS2 gene tends to be inactivated in prostate cancer rather than deleted, and so they are currently investigating strategies to alter RGS2 levels, which could ultimately lead to the development of new and better drugs for the treatment of advance prostate cancer.
Figure 1. RGS2 repression causes androgen-independent activation of androgen receptor. RGS2 protein, an endogenous inhibitor of GPCR functions, is selectively repressed in prostate cancer cells. Androgen receptor that is normally activated by androgens is now activated by GPCRs in the absence of androgens, leading to prostate cancer growth even under androgen ablation therapy.
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