Transforming growth factor-p (TGFp) inhibits the proliferation of epithelial cells in the prostate gland and acts as a tumor suppressor in the earlier stages of prostate cancer. However, prostate cancer cells develop resistance to TGFp inhibitory effects during the later stages of the disease. At that time, TGFp promotes angiogenesis and metastasis and hence is associated with the development of more aggressive form of this disease. We hypothesize that TGFp hypersecretion coupled with the loss of its inhibitory effects on proliferation leads to an earlier on set of more aggressive prostate cancers in African-American men. The proposed studies are designed to test this hypothesis. The cellular mechanisms involved in the development of resistance to inhibitory effects of TGFp on proliferation are not known but may involve components of TGFp signaling in transformed cells. Our preliminary studies show that TGFp inhibits proliferation of prostate cancer cell line DU145 but has no effect on proliferation of PC3 and LnCaP cells. Inhibition of proliferation in response to TGFp was associated with rapid decrease in the levels of Jun D in DU145 cells and overexpression of Jun D in these cells resulted in increased proliferation. On the other hand, over-expression of c-Jun resulted in decreased proliferation rate and increased sensitivity to TGFp. Our results suggest that decreasing Jun D levels may enhance c-Jun binding at the AP-1 site in TGFp treated cells to mediate inhibitory effects on cell proliferation. The proposed studies are designed to determine the role of TGFp during different stages of prostate cancer development and the role of c-Jun and Jun D in TGFp signaling during different stages and will focus on the following specific aims: 1. We will determine the expression patterns of TGFp isoforms, TGFp receptors, AP-1 and SMAD proteins in normal prostate epithelial cells and prostate cancer cells representing different stages of the disease, and their regulation by TGFp. 2. We will determine DMA binding activity of AP-1 and SMAD proteins in prostate cancer cells after treatment with TGFp and determine the roles of c-Jun and Jun D in prostate cancer cell proliferation. 3. We will also study the effects of TGFp on JNK activation and phosphorylation of Jun family members and determine their effects on cell proliferation. We will analyze c-Jun dependent gene expression in prostate cells in response to TGFp to identify down-stream signaling components involved in inhibition of cell proliferation.
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