Molecular Studies on Regulator of G-Protein Signaling 2 (RGS2) in Prostate Cancer

Project: Research project

Project Details

Description

PUBLIC ABSTRACT

The incidence of prostate cancer has risen by 60%-75% in the Western world in the last 15 years, and this figure is expected to rise by another 50% in the next 20 years. As prostate cancer progresses, it eventually changes to an androgen-independent prostate cancer that no longer relies on androgens (such as testosterone) for growth. Despite decades of intense laboratory and clinical investigation, there is still no cure for androgen-independent prostate cancer. Several lines of evidence suggest that androgen receptor (AR) that is normally activated by androgens is now activated in the absence of androgens, leading to androgen-independent progression of prostate cancer. Thus, understanding the regulation of AR activation is critical for overcoming the current therapeutic limitations for treating this disease. We recently reported that a newly discovered protein family called Regulators of G-protein Signaling (RGS) may function as novel regulators of AR in prostate cancer cells.

So far, over 20 mammalian RGS proteins have been identified, and they control many important cellular functions in neuronal, cardiovascular, and immunological systems. However, there is very little information available concerning the role of RGS proteins in the development and progression of prostate cancer. We found that the amount of a specific type of RGS protein, RGS2, is significantly reduced in human prostate tumor tissues as compared to normal prostate tissues. Selective loss of RGS2 protein was also found in several androgen-independent prostate cancer cell lines. Moreover, raising the levels of RGS2 but not other RGS proteins in prostate cancer cells inhibits androgen-independent AR activation and cell growth. This raises the possibility that RGS2 reduction plays an important role in androgen-independent prostate cancer progression. Our proposed studies utilize biochemical methods and cellular and molecular biology techniques to gain new information about the functions, mechanisms, and regulation of RGS2 in prostate cancer. We will first test whether changing the amount of RGS2 in the cells can accelerate or delay the prostate cancer cell progression both in vitro and in animal models. We will then define how RGS2 controls androgen-independent AR activation and prostate cancer cell growth at the molecular level. Finally, we will determine how the RGS2 expression is reduced and what level of RGS2 is found in different stages of prostate cancer. This knowledge will likely allow our colleagues and us to develop a novel test using RGS2 as a diagnostic marker for early detection of prostate cancer progression. In addition, the combination of tissue culture and animal work should greatly advance our understanding of molecular and cellular mechanisms of RGS proteins in the development and progression of prostate cancer, which could have clinical impact relatively quickly with respect to initial therapy. For example, our discovery predicts that any current or future clinical trial of a treatment for androgen-independent prostate cancer is predestined to fail if it does not bring about changes that restore RGS2 levels in the cancer cells. Thus, our studies could ultimately lead to new treatment strategies.

StatusFinished
Effective start/end date1/1/0612/31/06

Funding

  • U.S. Department of Defense: $258,300.00

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