Suppression of NFκB and its Regulated Gene Products by Oral Administration of Green Tea Polyphenols in an Autochthonous Mouse Prostate Cancer Model
This study examines the role of cell survival/apoptosis related proteins involved in NFκB signaling pathways and its associated events in GTP-induced chemoprevention of prostate cancer in TRAMP mice.
Mice were given 0.1% GTP as drinking fluid. Western blot and immunohistochemical analysis performed to examine NFκB and its regulated pathway in response to GTP.
Our data demonstrated increased expression of NFκB, IKKα, IKKβ, RANK, NIK and STAT-3 in dorso-lateral prostate of TRAMP mice as a function of age and tumor growth and continuous GTP infusion for 32 weeks resulted in substantial reduction in these proteins. The levels of transcription factor osteopontin, a non-collagenous extracellular matrix protein, were also downregulated. Inhibition of NFκB signaling is known to activate apoptotic and inhibit anti-apoptotic proteins. Therefore, we analyzed Bax and Bcl2 levels in the dorsolateral prostate of TRAMP mice fed GTP and observed a shift in balance between Bax and Bcl2 favoring apoptosis.
Based on the data we suggest that oral consumption of GTP might inhibit osteopontin and NFκB signaling that may contribute to induction of apoptosis observed in GTP fed TRAMP mice.
Key wordsgreen tea NFκB osteopontin RANK TRAMP
This original work for author’s laboratory was supported by US PHS Grants RO1 CA 78809; RO1 CA 101039, RO1 CA 120451 and O’Brian center Grant P50 DK065303-01.
- 10.S. Bettuzzi, M. Brausi, F. Rizzi, G. Castagnetti, G. Peracchia, and A. Corti. Chemoprevention of human prostate cancer by oral administration of green tea catechins in volunteers with high-grade prostate intraepithelial neoplasia: a preliminary report from a one-year proof-of-principle study. Cancer Res. 66:1234–1240 (2006).PubMedCrossRefGoogle Scholar
- 14.F. Garrouste, M. Remacle-Bonnet, C. Fauriat, J. Marvaldi, J. Luis, and G. Pommier. Prevention of cytokine-induced apoptosis by insulin-like growth factor-I is independent of cell adhesion molecules in HT29-D4 colon carcinoma cells-evidence for a NF-kappaB-dependent survival mechanism. Cell Death Differ. 9:768–779 (2002).PubMedCrossRefGoogle Scholar
- 18.A. C. Bharti, Y. Takada, S. Shishodia, and B. B. Aggarwal. Evidence that receptor activator of nuclear factor (NF)-kappaB ligand can suppress cell proliferation and induce apoptosis through activation of a NF-kappaB-independent and TRAF6-dependent mechanism. J. Biol. Chem. 279:6065–6076 (2004).PubMedCrossRefGoogle Scholar
- 21.M. H. Aziz, H. T. Manoharan, D. R. Church, N. E. Dreckschmidt, W. Zhong, T. D. Oberley, G. Wilding, and A. K. Verma. Protein kinase Cepsilon interacts with signal transducers and activators of transcription 3 (Stat3), phosphorylates Stat3Ser727, and regulates its constitutive activation in prostate cancer. Cancer Res. 67:8828–8838 (2007).PubMedCrossRefGoogle Scholar
- 25.B. B. Hafeez, S. Ahmed, N. Wang, S. Gupta, A. Zhang, and T. M. Haqqi. Green tea polyphenols-induced apoptosis in human osteosarcoma SAOS-2 cells involves a caspase-dependent mechanism with downregulation of nuclear factor-kappaB. Toxicol. Appl. Pharmacol. 216:11–19 (2006).PubMedCrossRefGoogle Scholar