Prostate cancer (PCA) is a second leading cause of cancer death in men over 65 years old. The progression of PCA from a latent to an aggressive form depends on the loss of androgen-dependency and the acquisition of the angiogenic phenotype. Consumption of green tea has been implicated in the lower incidence of various cancers including PCA in Chinese and Japanese men in a number of epidemiological studies. In recent laboratory studies, green tea catechins have been shown to inhibit the growth of PCA cell lines and the neovascularization in green tea drinking mice. It has been shown that (-)- epigallocatechin-3-gallate (EGCG), one of green tea catechins, is the most potent in inhibiting tumor cell proliferation and angiogenesis. Tissue hypoxia is a key player in angiogenesis in part via the induction of angiogenic factor expression. It is our hypothesis that EGCG can prevent hypoxia-induced angiogenesis via the inhibition of angiogenic factor expression, ultimately inhibiting cancer cell proliferation and metastatic spread. To our knowledge no prior study has assessed the effect of EGCG on hypoxia-induced angiogenesis. In this application, we will test this hypothesis using human PCA cell lines, LNCaP and DU-145, and in vivo studies using a transgenic animal model TRAMP (transgenic adenocarcinoma mouse prostate), that mimics the progressive form of human PCA. We will characterize the effect of EGCG on the expression of angiogenic factors (VEGF, IL-8, endothelin-1) by prostate cancer cells under normoxia and hypoxia. We will also determine if the expression of hypoxia induced factor (HIF)-lc_ and DNA binding activity of HIF-1 transcription factor complex can be regulated by EGCG under normoxia and hypoxia. HIF-l-mediated transcription activation will be investigated in EGCG treated cells under hypoxia. Lastly, we will investigate the angiogenesis and HIF-lc_ expression in prostate tumors in TRAMP mice drinking EGCG-containing water. We believe that the outcome of this application will help further our understanding of antiangiogenic mechanism of EGCG and provide preclinical data on EGCG as a complimentary and alternative medicine agent to be used to prevent progression of PCA into angiogenic and metastatic cancer, thus prolonging the survival and quality of PCA patients.
| Thomas, Rusha; Kim, Myoung H (2009) A HIF-1alpha-dependent autocrine feedback loop promotes survival of serum-deprived prostate cancer cells. Prostate 69:263-75 |
| Thomas, Rusha; Kim, Myoung H (2008) HIF-1 alpha: a key survival factor for serum-deprived prostate cancer cells. Prostate 68:1405-15 |
| Kim, Myoung H (2008) Protein phosphatase 1 activation and alternative splicing of Bcl-X and Mcl-1 by EGCG + ibuprofen. J Cell Biochem 104:1491-9 |
| Kim, Myoung H; Chung, Jaegwon (2007) Synergistic cell death by EGCG and ibuprofen in DU-145 prostate cancer cell line. Anticancer Res 27:3947-56 |
| Thomas, Rusha; Kim, Myoung H (2007) Targeting the hypoxia inducible factor pathway with mitochondrial uncouplers. Mol Cell Biochem 296:35-44 |
