Molecular Mechanisms Underlying Chemopreventive Effects of Zerumbone, Curcumin and Phloretin on Mouse Skin Carcinogenesis

Abstract

Human body is challenged with a wide array of xenobiotics many of which can exert chemical stresses and it cause many disease including cancer. In order to cope with noxious insults, our body operates a distinct set of defence mechanisms. Among them, induction of cytoprotective proteins plays a key role, which eliminate or detoxify those hamful chemicals and their metabolites and is believed to be an important means of protecting carcinogenesis. However this induction is transient, reinforced expression of cytoprotective proteins is more effective defense mechanism against carcinogenesis. NF-E2-related factor 2 (Nrf2) is a transcription factor that has emerged as a critical mediator in induction of various cytoprotective proteins. For over a decade, the regulation of Nrf2 has been investigated extensively and Keap1 was identified as the critical regulator of Nrf2. Under normal conditions, Nrf2 is degraded continuously by the Cullin3-Rbx1 E3 ubiquitin ligase to maintain low basal leves of Nrf2. Cullin3 serves as a scaffolding protein that is associated to both Rbx1 and Keap1. Conversely, under stressed condition, the ablility of the Cullin3-Rbx1 E3 ubiquitin ligase to ubiquitinate Nrf2 is abrogated, allowing Nrf2 to translocate into the nucleus, and initiate the transcription of cytoprotective genes. Many recent papers reported that cytoprotective proteins are induced by nature occurring agents through Nrf2 activation and cancer prevention can be achived by consumption of these dietary phytochemicals. Thus, the success of chemoprevetion by induction cytoprotective protein using phytochemicals demands understanding of exact molecular mechanisms that mediates this induction. Another promisimg strategy for successful chemoprevention by nature occurring agents is inhibition of inflammatory. Cyclooxygenase-2 (COX-2), the key proinflammatory enzyme that catalyzes the rate-limiting step in prostaglandin (PG) biosynthesis, has been implicated in carcinogenesis. An abnormally elevated COX-2 expression has been observed frequently in multiple malignancies. Thus, inhibition of COX-2 by phytochemicals is one of successful stretagy for cancer prevention