Abstract 1694 Combined analysis of gene expression microarray data from Polyphenon E-treated prostate cancer cells identifies significant gene expression changes

Polyphenon E (Poly E) is a standardized, caffeine-free green tea extract with defined polyphenol content. Oral Poly E administration confers chemoprotective activity against prostate cancer (PCa) progression in the TRAMP model of human PCa. Poly E also has limited activity against human PCa, but only in those previously diagnosed with atypical small acinar proliferation or high-grade prostate intraepithelial neoplasia. The molecular mechanisms underpinning Poly E chemopreventive activities against PCa are not fully understood. We hypothesized Poly E treatment of PCa cells induces gene expression changes, which could involve molecular mechanisms underpinning the limited Poly E chemoprevention activity against PCa. DU145, LNCaP, and PC-3 cells were cultured in complete growth media supplemented with varied Poly E concentrations (DU145 and PC-3: 0, 100, 200, or 300 mg/L; LNCaP: 0, 15, 30, 40) for 24 hr. RNA was isolated for comparative gene expression microarray (untreated; 0 mg/L Poly E vs. medium-level; 200 mg/L Poly E for DU145 and PC-3, 30 mg/L for LNCaP). DU145, LNCaP, and PC-3 microarray data from 54,613 genes were combined and filtered for at least > 2-fold expression level changes. In the combined analysis of these data, 735 increased gene expression > 2-fold and 1107 decreased gene expression > 2-fold, respectively. Of these 1842 genes identified with > 2-fold expression level changes, the gene expression changes observed across these three PCa cell lines were significant (p<0.05) for 187 genes. From these 187 genes, 17 were selected for further studies based upon the significant gene expression changes and their known biological function: ATM (-3.54 fold change, p=0.0145), BCL2L11(+ 2.2 fold change, p=0.0143), CCSER2 (+ 4.31 fold change, p=0.0163), DDIT3 (+ 3.72 fold change, p=0.0405), ERCC8 (- 2.30 fold change, p=0.0480), HDAC4 (-3.26 fold change, p=0.0250), HDAC8 (2.93 fold change, p=0.0411), HRK (+ 2.24 fold change, p=0.0347), KDM7A (+ 2.64 fold change, p=0.0299), MXD1 (+ 2.33 fold change, p=0.0393), MXI1 (+ 2.05 fold change, p=0.0241), SEC42A (+ 3.40 fold change, p=0.0461), SEC62 (- 2.19 fold change, p=0.0487), SESN2 (+ 3.66 fold change, p=0.0386), SOD2 (+ 2.10 fold change, p=0.0476), TRIB3 (+ 3.20 fold change, p=0.0176), UBE3B (+ 2.11 fold change, p=0.0324), and XIAP (+ 2.54 fold change, p=0.0317). Among these 17 genes, three are involved in apoptosis (BCL2L11, HRK, XIAP), two in intracellular trafficking of vesicles (SEC42A, SEC62), while other genes identified involve DNA damage response (ATM, DDIT3, ERCC8), gene expression (HDAC4, HDAC8, KDM7A), cell cycle control (MXD1, MXI1), cellular stress response (SESN2, SOD2, TRIB3), and ubiquitination (UBE3B). Most of these 17 genes have been reported to have some involvement in prostate cancer, except three genes (CCSER2, SEC42A, UBE3B). These data provide insights into the program of gene expression changes induced by Polyphenon E exposure in multiple PCa cell lines. The cellular processes of apoptosis, intracellular trafficking, as well as control of cell-cycle, cell-growth, and gene expression are all implicated by the data as playing a role in the PCa cellular response to Polyphenon E treatments. This combined analysis of gene expression microarray data across multiple PCa cell lines provides novel targets for future molecular investigations. The work was supported by a Dana Research grant award (PI: LMC) from The University of Tampa. This work was also partially funded by Polyphenon Pharma Mitsui Norin Co., Japan (PI: JYP). This work was partially supported by the Molecular Genomics Core at the Moffitt Cancer Center and funded in part by Moffitt's Cancer Center Support Grant (P30-CA076292).