Androgenic Inactivation of FOXO1 in Prostate Cancer

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DESCRIPTION (provided by applicant): Prostate cancer is the second leading cause of cancer death in the United States. Cancer cells in the prostate depend on androgens for growth and survival. Mitogenic effects of androgens have been linked to their modulation of cell cycle regulatory molecules such as cyclin-dependent kinase 2 and 4 (CDK2 and CDK4). However, the molecular mechanisms for androgen-mediated cell survival are not fully elucidated. We and others have shown that androgens promote prostate cancer survival by antagonizing the function of PTEN, a tumor suppressor protein. Further studies have revealed that androgens block PTEN signaling by directly inhibiting the function of the forkhead transcription factor FOXO1 (FKHR), a key downstream target of PTEN. Our preliminary data demonstrate that CDK2 interacts with and phosphorylates FOXO1 in vitro and in vivo. CDK2 inhibits the function of FOXO1 through phosphorylation of serine 249. Importantly, CDK2- mediated phosphorylation and inhibition of FOXO1 can be reversed upon DNA damage induced by chemotherapeutic agents and irradiation. In view of the roles of androgen-mediated proliferation and survival and the anti-tumor effect of the interaction between androgen ablation and radiation therapy in the clinic, we hypothesize that CDK2-mediated inactivation of FOXO1 plays an important role in androgen-stimulated proliferation, survival, and oxidative stress in prostate cancer cells. To test this hypothesis, we propose to determine (1) whether CDK2-mediated phosphorylation of FOXO1 plays an essential role in androgen- stimulated proliferation and survival of prostate cancer cells; (2) whether androgen-induced phosphorylation of FOXO1 inhibits FOXO1 transcriptional activity in prostate cancer cells; (3) whether activation of FOXO1 is a key factor that mediates the synergistic anti-tumor effect of androgen ablation and radiation therapy. The findings from this work will provide new insights into the working mechanisms of androgen-induced proliferation and survival of prostate cancer cells. Moreover, they should enhance our understanding of the underlying mechanisms of the therapeutic advantage of androgen ablation and radiation therapy in the clinic.