Regulation of AR Function by NOS. The androgen receptor (AR) is a ligand-controlled transcription factor that is responsible for mediating all biological actions of androgens in target issues, including male sexual development and maintenance of male sex characteristics. Mutations in the AR gene can cause the androgen-insensitivity syndrome that affects normal male morphogenesis, and unregulated AR signaling has been linked to the development of Kennedy's disease, a progressive degenerative condition affecting lower motor neurons. Significantly, clinical- and laboratory-based evidence demonstrates that AR plays a critical role in prostate cancer, the second leading cause of cancer death in men. Recent work has identified activating mutations in AR, and transgenic animals harboring the mutated AR develop prostatic intraepithelial neoplasia that progress to invasive prostate cancer. Mechanisms involved in the regulation of AR dysfunction (and, therefore, contribution to human disease) remain incomplete. Our preliminary data show that NOS is endogenously expressed in prostate cancer cells, and that overexpression of NOS in LNCaP cells attenuates the androgen-induced AR activation, and inhibits cell proliferation in vitro and xenograft tumor growth in animals. Pharmacologic inhibition of NOS activity enhances androgen-regulated AR activation in vitro, and knockdown of NOS expression with siRNA increases the AR association with prostate-specific antigen promoter. The AR forms a complex with NOS and is post-translationally modified by S- nitrosylation (i.e. the covalent attachment of a NO group to cysteine residue). We propose two specific aims to test the hypothesis that NOS and its product NO regulate AR function to control prostate cancer cell proliferation: [i] to establish effects of NOS expression and pharmacologic NOS inhibitors and NO donors on AR function, and prostate cell proliferation, and [ii] to elucidate the mechanisms by which NOS and NO regulate AR function and prostate cell proliferation with emphasis on AR S-nitrosylation. The targeted activation of NOS, or treatment with NO donors is hoped to serve as a specific molecular therapy tool to successfully treat prostate cancer. Prostate cancer is the leading cause of cancer-related death of American men, and androgen receptor is involved in the initiation and progression of the disease. We found that androgen receptor is modified by S-nitrosylation, which inhibits its function. The targeted activation of NOS, or treatment with NO donors may serve as a specific molecular therapy tool to successfully treat patients with prostate cancer. ? ? ?
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