Peracetylated (-)-epigallocatechin-3-gallate (AcEGCG) potently prevents skin carcinogenesis by suppressing the PKD1-dependent signaling pathway in CD34+ skin stem cells and skin tumors
Menée sur un modèle murin, cette étude montre que l'épigallocatéchine gallate peracétylée peut avoir un effet chimiopréventif sur la carcinogenèse de la peau en supprimant la voie de signalisation dépendante de la protéine kinase D1 dans les cellules souches CD34 + et les cellules tumorales de la peau
During the process of skin tumor promotion, expression of the cutaneous cancer stem cell (CSC) marker CD34+ is required for stem cell activation and tumor formation. A previous study has shown that activation of protein kinase D1 (PKD1) is involved in epidermal tumor promotion; however, the signals that regulate CSCs in skin carcinogenesis have not been characterized. The present study was designed to investigate the chemopreventive potential of AcEGCG on 7,12-dimethylbenz[a]-anthracene (DMBA)-initiated and 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted skin tumorigenesis in ICR mice and to elucidate the possible mechanisms involved in the inhibitory action of PKD1 on CSCs. To clarify the role of PKD1 in cell proliferation and tumorigenesis, we studied the expression and activation of PKD1 in CD34+ skin stem cells and skin tumors. We found that PKD1 was strongly expressed in CD34+ cells and that pretreatment with AcEGCG markedly inhibited PKD1 activation and CD34+ expression. More importantly, pretreatment with AcEGCG remarkably suppressed NF-κB, cAMP-responsive element binding protein (CREB) and CCAAT-enhancer-binding protein (C/EBPs) activation by inhibiting the phosphorylation of c-Jun-N-terminal kinase 1/2, p38, and phosphatidylinositol 3-kinase (PI3K)/Akt and by attenuating downstream target gene expression, including inducible nitric oxide synthase (iNOS), cyclooxygenase-2, ornithine decarboxylase, and vascular endothelial growth factor (VEGF). Moreover, this is the first study to demonstrate that AcEGCG is a CD34+ and PKD1 inhibitor in the multi-stage mouse skin carcinogenesis model. Overall, our results powerfully suggest that AcEGCG could be developed into a novel chemopreventive agent and that PKD1 may be a preventive and therapeutic target for skin cancer in clinical settings.
http://carcin.oxfordjournals.org/content/early/2013/02/04/carcin.bgt042.abstract