Abstract 5570: p53-dependent and p53-independent responses by green tea polyphenols in human prostate cancer cells

Abstract

Abstract Green tea polyphenols (GTP) have been shown to provide protection against various preclinical models of prostate cancer. Recent studies conducted with GTP have provided evidence that it is effective at the initial stages of cancer development and could delay disease progression by perturbation of cell cycle and induction of apoptosis. Understanding the mechanisms that control GTP-mediated cellular responses is central to improving the therapeutic index and to encounter successfully the resistance frequently acquired during cancer therapy. p53, a tumor suppressor and a sequence-specific transcription factor senses a variety of stress signals to cells through multiple upstream signaling pathways and induces cell cycle arrest and/or apoptosis by modulating its downstream targets depending on the extent of cell damage, thus playing a central role in maintaining cellular homeostasis. p53 is either mutated or has defective signaling in most human cancers and might be one of the critical determinants for the GTP-mediated chemosensitivity of prostate tumors. We examined cell cycle and apoptosis related cellular responses to GTP exposure using human prostate cancer LNCaP cell which possess functional p53 and its variant where p53 was knocked out using shp53RNA. Exposure to various concentration of GTP (20, 40 and 80 mcg/mL) exhibited differential dose and time dependent resistance in these cells. Treatment of LNCaP cell containing empty vector with GTP caused cell cycle arrest and apoptosis which was associated with induction of p53 and its downstream cell cycle arrest and pro-apoptotic proteins p21, BIM and PUMA. In contrast, cell growth inhibition, cell cycle perturbation and induction of apoptosis in LNCaPshp53 cells was achieved at higher concentration of GTP, primarily because p53 knockdown resulted in activation of Akt phosphorylation at serine473 causing increased survival of cancer cells. To generate functional networks, protein expression of a number of genes involved in cell cycle and apoptosis, such as p21, Bad, Bax, Bcl-2, Bid, Bim, cIAP, XIAP, FAS, FADD, pFADD, p73, caspases 3, 8 and 9 was studied. Our results support the role of both p53-dependent and p53-independent responses in GTP-mediated cell cycle arrest and apoptosis of prostate cancer cells. These findings highlight the differential effect of Akt on p53 functions which seems to be responsible for the differential regulation of cell death by GTP in prostate cancer cells. Our findings become relevant as alterations in the protein expression profile could be used as in vivo markers in developing a molecular platform that could reliably monitor the responses of human prostate cancer cell populations to GTP-mediated therapeutic interventions, thereby providing clinical protocols with novel and powerful molecular tools for a more efficient and successful management of human prostate malignancies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5570. doi:10.1158/1538-7445.AM2011-5570