Prostrate carcinoma is the most common malignancy and the second leading cause of cancer death among men. One of the contributing factors to this high mortality rate is due to the fact that human prostrate cancers are extremely resistant to gamma radiation and chemotherapies, which kill cells by the induction of apoptosis. Thus, malignant prostate epithelium relapse within 3 years with an androgen-dependent and recurrent prostrate cancer. In this proposal we have identified two distinct cell survival pathway utilized by androgen-dependent and recurrent prostate cancer. The CWR22 human prostate xenograft model will be used to understand the molecular mechanisms governing the anti-apoptotic pathways involved in prostrate cancer. In our preliminary data we demonstrate that the transcription factor NF-kappaB provides a cell survival provides a cell survival function in prostate cells and show that NF-kappaB activity correlates with nuclear androgen receptor (AR) expression. These findings are important because NF-kappaB has been recently demonstrated to promote oncogene-mediated tumorigenesis by inhibiting apoptosis and because the presence of nuclear AR in recurrent prostate cancer may be critical for cell survival in the absence of testicular androgens. To understand the mechanisms regulating recurrent prostate cancer, we analyzed the expression of anti-and pro-apoptotic proteins in the androgen-independent CWR22R model. Compared to CWR22 tumors, androgen-independent CWR22R tumors displayed elevated Bcl-2 and c-Myc proteins as well as cytoplasmic localization of the tumor suppressor protein p53. The upregulation of Bcl- 2 has significant implications in prostate cancer since the overexpression of Bcl-2 is known to block androgen ablation-induced apoptosis. These results are also important since Bcl-2 and c-Myc oncoproteins are commonly overexpressed in human prostatic carcinomas and because Bcl-2 is able to overcome p53-dependent apoptosis by cooperating with c-Myc to subcellularly traffic p53 to the cytoplasm. The two major goals of this proposal are to: (1) determine whether NF-kappaB activity is regulated by AR and determine if NF-kappaB provides an anti-apoptotic cell survival function in androgen-dependent as well as recurrent prostate cancer, and (2) elucidate whether Bcl-2 and c-Myc are associated with androgen- independent growth of prostate cancer and whether this involves the inactivation of the p53 tumor suppressor protein.
Aim 1 will determine whether NF-kappaB is activated by AR-signaling, whether NF-kappaB is required for survival of prostate epithelium by blocking the induction of apoptosis and whether combined therapies employing NF-kappaB inhibitors and chemotherapeutic agents will improve therapy for prostate tumors.
Aim 2 will employ specific inhibitors of Bcl-2 to determine whether this oncoprotein is required for the survival of androgen-independent prostate cancer.
Aim 3 will determine whether the expression of c-Myc is required for androgen-independent tumor growth and whether co-expression of c-Myc and Bcl-2 results in the inactivation of p53 through cytoplasmic sequestration. These studies have important implications for understanding the oncogenic roles of dysregulated Bcl-2, c-Myc, and NF-kappaB in prostate cancer and may suggest novel approaches for treatment.
Showing the most recent 10 out of 47 publications
