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Every year over 1 million cases of nonmelanoma skin cancer are diagnosed in the USA alone, and chronic ultraviolet light (UV) exposure is widely believed to be the major cause. Cyclooxygenase-2 (COX-2) is a key enzyme in the conversion of arachidonic acid to prostaglandins and multiple lines of evidence demonstrate that induction of COX-2 expression and subsequent increase in prostaglandins contribute to skin cancer development. Our previous studies have shown that exposure to UVB strongly increases COX-2 protein expression in mouse 308 keratinocytes, which is inhibited by apigenin, a nonmutagenic bioflavonoid that has been proven to prevent mouse skin carcinogenesis induced by both chemical carcinogens and UV exposure. One pathway by which apigenin inhibits UV-induced COX-2 expression is through modulation of USF transcriptional activity in the 5’ upstream region of the COX-2 gene. Here, we reported that apigenin treatment increased the half-life of COX-2 mRNA. To understand this discordance, we further examined the mechanisms underlying COX-2 mRNA stability and protein translation, and found that the AU-rich element (ARE) within the 3’ untranslated region (3’-UTR) of COX-2 mRNAwas important for COX-2 mRNA stability and translation efficiency: it increased luciferase reporter gene activity after UVB irradiation and apigenin prevented this activity. Furthermore, we demonstrated that two RNA binding proteins, HuR and TIAR, were associated with endogenous COX-2 mRNA in 308 keratinocytes, and apigenin treatment increased their localization to cell cytoplasm and the formation of stress granules associated with TIAR. More importantly, reduction of HuR levels by siRNA inhibited apigenin-mediated stabilization of COX-2 mRNA. Cells expressing TIAR siRNA showed marked resistance to apigenin’s ability to inhibit UVB-induced COX-2 expression. Taken together, these results indicate that in addition to transcriptional regulation, another mechanism by which apigenin prevents COX-2 expression is through mediating TIAR’s suppression of COX-2 mRNA translation.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA