Tumor Suppressor Function of Androgen Receptor Coactivator ARA70α 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, ARA70β, promotes prostate cancer cell growth and invasion. Here we report that the full length ARA70α, 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 ARA70α 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 ARA70α, facilitating the growth of LNCaP cells. The tumor suppressor function of ARA70α is consistent with our previous findings that ARA70α expression is decreased in prostate cancer cells compared with benign prostate. ARA70α also reduced the invasion ability of LNCaP cells. Although growth inhibition by ARA70α is AR-dependent, the inhibition of cell invasion is an androgen-independent process. These results strongly suggest that ARA70α functions as a tumor suppressor gene.