Suppression of NFκB and its regulated pathways by oral administration of green tea polyphenols in an autochthonous mouse model of prostate cancer

Proc Amer Assoc Cancer Res, Volume 47, 2006 4893 Green tea polyphenols (GTP) possess strong chemopreventive properties against a variety of animal tumor models and in some human epidemiological studies. We have earlier shown that oral infusion of GTP inhibits the growth and progression of prostate cancer (PCa) in transgenic adenocarcinoma of mouse prostate (TRAMP) model and that inhibition of insulin like growth factor-I (IGF-I) signaling plays a major role in this process. IGF-I is known to stimulate sustained activation of NFκB and constitutive activation of NFκB occurs during PCa progression in humans and TRAMP. In this study we examined the role of proteins involved in NFκB signaling and other associated molecules during GTP mediated chemoprevention of PCa in TRAMP mice. Four weeks old male TRAMP mice were fed orally with 0.1% GTP as the sole source of drinking fluid throughout and water-fed animals served as controls. The animals were sacrificed at 4, 8, 20 and 28 weeks following GTP feeding and dorsolateral prostate tissues were collected. GTP feeding to TRAMP resulted in significant inhibition of constitutive NFκB activation. This corresponded with suppression of receptor activator of NFκB (RANK), known to up-regulate anti-apoptotic proteins. Inhibition of NFκB accompanied inhibition of NFκB inducing kinase (NIK), IKKα, IκBα and phospho-NFκB. This inhibition of NFκB signaling was observed in GTP-fed animals at all time points examined. Osteopontin, an extracellular matrix protein secreted by infiltrating macrophages and tumor cells, plays a role in the transition to metastatic PCa and is expressed at high levels in poorly differentiated carcinomas in TRAMP. Since osteopontin is known to stimulate tumor growth through activation of NFκB, we next determined the expression of osteopontin during GTP-mediated inhibition of PCa. An inhibition in the expression of osteopontin by oral infusion of GTP, particularly at 24 and 32 weeks of age was observed. Increased resistance to apoptosis also occurs due to constitutive activation of signal transducer and activator of transcription (STAT)-3. We observed an increased expression of STAT-3 in TRAMP as a function of age that was inhibited by oral infusion of GTP. Inhibition of NFκB signaling is known to activate apoptotic and inhibit anti-apoptotic proteins. Therefore, we next analyzed Bax and Bcl2 levels in the dorsolateral prostate of TRAMP mice fed GTP. We observed increasing levels of Bax and decreasing levels of Bcl2 in each treatment group of GTP-fed, tilting the balance between Bax and Bcl2 in favor of apoptosis. Taken together, our data strongly suggests that oral consumption of GTP inhibits NFκB signaling which may contribute to induction of apoptosis observed in GTP-fed TRAMP mice.