Prostate carcinoma is the most common malignancy and the second leading cause of cancer death among men. In advanced prostate cancer, 98% of patients who have undergone androgen deprivation relapse within 3 years with an androgen-independent cancer. Importantly, most androgen- independent prostate cancers display dysregulated bcl-2 expression. Bcl-2 over-expression confers resistance to apoptosis following androgen withdrawal which suggests that prostate cancer may survive androgen deprivation by the over-expression of this oncoprotein. Furthermore, c-myc is over-expressed in hyperplastic and malignant prostate epithelium. Over- expression of Bcl-2 when accompanied with c-Myc is transforming, perhaps due to the modulation of p53 tumor suppressor function. In this research proposal, the CWR22 human prostate xenograft model will be used to understand the molecular mechanism governing the progression of androgen- independent prostate cancer. Preliminary data presented in this proposal demonstrate that, unlike the androgen-dependent CWR22 tumor, androgen- independent CWR22R tumors are resistant to androgen deprivation-induced apoptosis, display significant levels of endogenous Bcl-2 and c-Myc, and exhibit cytoplasmically localized p3 protein. In addition to the gene products, such as Bcl-2, which are known to directly modulate cell survival, other factors can regulate cellular responses to apoptotic stimuli. Recently our laboratory has demonstrated that the transcription factor NF-kappaB can potentiate cellular transformation by overcoming apoptosis. Importantly, or preliminary data indicate that NF-kappaB is required for cell survival in malignant prostate cells. The three major goals of this proposal are to determine whether (1) Bcl-2 is required for progression of androgen-independent prostate cancer, (2) Bcl-2 and c-Myc are associated with androgen-independence of prostate cancer by inactivating the p53 tumor suppressor protein, and (3) NF-kappaB provides a cell survival function in androgen-independent prostate cancer.
Aim 1 will employ adenoviral-mediated gene delivery of sense and antisense Bcl-2 constructs to determine whether this oncoprotein is required for the survival of androgen-independent prostate cancer.
Aim 2 will determine whether co-expression of c-Myc and Bcl-2 results in the inactivation of p53 through cytoplasmic sequestration.
Aim 3 will determine whether NF- kappB is required for survival of androgen-independent prostate epithelium and whether combined therapies employing NF-kappaB inhibitors and chemotherapeutic agents may reduce tumor growth in androgen-independent (CWR22R) and metastatic (mCWR22) xenografts. These studies have important implications for understanding the oncogenic roles of dysregulated Bcl-2, c-Myc, and NF-kappaB in the growth of androgen-independent prostate cancer and may suggest novel approaches for treatment.
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