Taxifolin suppresses UV-induced skin carcinogenesis by targeting EGFR and PI3K. Cancer Prev Res (Phila)
The Hormel Institute, University of Minnesota, 801 16 Ave NE, Austin, MN 55912. .Cancer Prevention Research (Impact Factor: 4.44). 07/2012; 5(9):1103-14. DOI: 10.1158/1940-6207.CAPR-11-0397
Skin cancer is one of the most commonly diagnosed cancers in the United States. Taxifolin reportedly exerts multiple biologic effects, but the molecular mechanisms and direct target(s) of taxifolin in skin cancer chemoprevention are still unknown. In silico computer screening and kinase profiling results suggest that the EGF receptor (EGFR), phosphoinositide 3-kinase (PI3K), and Src are potential targets for taxifolin. Pull-down assay results showed that EGFR, PI3K, and Src directly interacted with taxifolin in vitro, whereas taxifolin bound to EGFR and PI3K, but not to Src in cells. ATP competition and in vitro kinase assay data revealed that taxifolin interacted with EGFR and PI3K at the ATP-binding pocket and inhibited their kinase activities. Western blot analysis showed that taxifolin suppressed UVB-induced phosphorylation of EGFR and Akt, and subsequently suppressed their signaling pathways in JB6 P+ mouse skin epidermal cells. Expression levels and promoter activity of COX-2 and prostaglandin E(2) (PGE(2)) generation induced by UVB were also attenuated by taxifolin. The effect of taxifolin on UVB-induced signaling pathways and PGE(2) generation was reduced in EGFR knockout murine embryonic fibroblasts (MEF) compared with EGFR wild-type MEFs. Taxifolin also inhibited EGF-induced cell transformation. Importantly, topical treatment of taxifolin to the dorsal skin significantly suppressed tumor incidence, volume, and multiplicity in a solar UV (SUV)-induced skin carcinogenesis mouse model. Further analysis showed that the taxifolin-treated group had a substantial reduction in SUV-induced phosphorylation of EGFR and Akt in mouse skin. These results suggest that taxifolin exerts chemopreventive activity against UV-induced skin carcinogenesis by targeting EGFR and PI3K. Cancer Prev Res; 5(9); 1103-14. ©2012 AACR.
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ABSTRACT: Carcinogenesis is a multistage process involving hundreds of genes and gene products that regulate various cellular functions. The prevailing opinion today is that cancer might be prevented with small molecules that target specific or multiple cancer genes, signaling proteins and transcription factors. Some promising small molecule inhibitors include various dietary factors. Many of these factors appear to act on multiple tumor-associated cellular pathways with potent anticancer activity, low toxicity and limited adverse side effects. Combining agents or using individual agents that target multiple pathways is a strategy that is gaining acceptance. Powerful modern technologies are needed to accelerate the process of drug discovery especially to find compounds that can suppress multiple cellular signaling pathways. Combining supercomputer technologies, such as in silico screening, with protein structure determination and experimental laboratory validation assays to identify multiple protein targets of anticancer compounds is an example of technologies needed. This paper highlights two of the signaling pathways known to play an important role in carcinogenesis and describes the computational strategies used to identify small molecule inhibitors of these pathways. Finally, examples of molecules and their protein targets, which have been identified and validated by these combinational strategies for chemoprevention, are presented.
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