FIG. 7.

A simplified illustration shows the pathogenesis in human PCa and the role of Nrf2 in TRAMP PCa model. (A) Normal prostatic epithelial cells may be subjected to the chronic inflammation and oxidative stress in addition to other factors such as aging and diets. For more detailed molecular pathogenesis of PCa, please refer to Nelson et al. (117). As found in CRC, inflammation is believed to be one of the key events before the formation of PCa, and proliferative inflammatory atrophy is a precursor to PIN and PCa. (B) The TRAMP mouse is an autochthonous transgenic animal model of PCa that recapitulates the whole spectrum of human prostate tumorigenesis from the earliest PIN lesions to androgen-independent disease (71). Without chemical or hormonal treatment, 100% of male TRAMP develops PCa and progress from PIN to histological cancer to carcinoma metastasis to lymph nodes, lungs, and occasionally bones sequentially over 12–28 weeks (39, 40). A schematic illustration of the putative role of inflammation and oxidative stress and their effect on Nrf2 and related phase II detoxifying and antioxidant enzymes in prostate carcinogenesis in TRAMP mice. Effective chemopreventive compounds such as COX-2 inhibitors and gamma tocopherol-enriched mixed tocopherols significantly downregulated proinflammatory genes and upregulated expression of Nrf2 and its related detoxifying and antioxidant enzymes, respectively, preventing PCa carcinogenesis in TRAMP mice, especially when they are given early before the formation of PIN. CRC, colorectal cancer; Nrf2, NF-E2-related factor 2; PCa, prostate cancer; PIN, prostatic intraepithelial neoplasia; TRAMP, transgenic adenocarcinoma mouse prostate.