Prostate cancer is one of the major health problems affecting American males. 1,25-dihydroxyvitamin D3 (1,25D), has been demonstrated to inhibit growth of both androgen-dependent and androgen-independent prostate cancer cell lines. However, mechanisms by which 1,25D exposure leads to decreases in prostate cancer cell growth are not fully understood. It is also not clear whether androgen receptor (AR), which is expressed in both androgen-dependent and androgen-independent tumors, affects the ability of prostate cancer to respond to 1,25D and other vitamin D receptor (VDR) agonists. It is my hypothesis that 1) AR is not required for 1,25D-induced growth inhibition, and 2) growth inhibition is mediated by alterations in autocrine growth factor signaling. The goal of this project is to test this hypothesis by examining the role of AR and autocrine growth factors in 1,25D stimulated growth inhibition.
Under Aim 1, I will explore the importance of AR in 1,25D-induced growth inhibition by testing effects of VDR agonists in LNCaP cells that express very low AR levels. The experiments under Aim 2 will examine the role of autocrine growth factors in 1,25D growth repression by first exploring whether growth inhibition by 1,25D requires upregulation of IGF binding protein-3. In addition, proteomics and DNA microarray analysis will be used to identify other growth factor signaling systems that mediate 1,25D-induced growth inhibition.
Aim 3 will use a nude mouse xenograft model to examine the effect of VDR agonists on androgen-independent prostate tumor growth in vivo. In addition, these studies will explore whether circulating androgen levels or tumor location affect tumor response to VDR agonists. From the proposed studies, information will be gained that will provide further insight into the mechanisms by which VDR agonists regulate prostate cancer cell growth and the value of VDR agonists as chemotherapeutic agents for prostate cancer.
| Stewart, Lamonica V; Weigel, Nancy L (2005) Role of insulin-like growth factor binding proteins in 1alpha,25-dihydroxyvitamin D(3)-induced growth inhibition of human prostate cancer cells. Prostate 64:9-19 |
| Stewart, LaMonica V; Lyles, Besstina; Lin, Ming-Fong et al. (2005) Vitamin D receptor agonists induce prostatic acid phosphatase to reduce cell growth and HER-2 signaling in LNCaP-derived human prostate cancer cells. J Steroid Biochem Mol Biol 97:37-46 |
