Tumor suppressor function of androgen receptor coactivator ARA70alpha in prostate cancer.

Androgen receptor (AR), a member of the steroid receptor family, is a transcription factor that has an important role in the regulation of both prostate cell proliferation and growth suppression. AR coactivators may influence the transition between cell growth and growth suppression. We have shown previously that the internally spliced ARA70 isoform, ARA70 beta, promotes prostate cancer cell growth and invasion. Here we report that the full length ARA70 alpha, in contrast, represses prostate cancer cell proliferation and anchorage-independent growth in vitro and inhibits tumor growth in nude mice xenograft experiments in vivo. Further, the growth inhibition by ARA70 alpha is AR-dependent and mediated through induction of apoptosis rather than cell cycle arrest. Interestingly, AR with T877A mutation in LNCaP cells decreased its physical and functional interaction with ARA70 alpha, facilitating the growth of LNCaP cells. The tumor suppressor function of ARA70 alpha is consistent with our previous findings that ARA70 alpha expression is decreased in prostate cancer cells compared with benign prostate. ARA70 alpha also reduced the invasion ability of LNCaP cells. Although growth inhibition by ARA70 alpha is AR-dependent, the inhibition of cell invasion is an androgen-independent process. These results strongly suggest that ARA70a functions as a tumor suppressor gene. (Am J Pathol 2010, 176:1891-1900; DOI: 10.2353/ajpath.2010.090293)