title: Peracetylated (-)-epigallocatechin-3-gallate (AcEGCG) potently prevents skin carcinogenesis by suppressing the PKD1-dependent signaling pathway in CD34+ skin stem cells and skin tumors.
abstract: 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. This study was designed to investigate the chemopreventive potential of peracetylated (-)-epigallocatechin-3-gallate (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. We demonstrated that topical application of AcEGCG before TPA treatment can be more effective than EGCG in reducing DMBA/TPA-induced tumor incidence and multiplicity. Notably, AcEGCG not only inhibited the expression of p53, p21, c-Myc, cyclin B, p-CDK1 and Cdc25A but also restored the activation of extracellular signal-regulated kinase 1/2 (ERK1/2), which decreased DMBA/TPA-induced increases in tumor proliferation and mitotic index. 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 nuclear factor-kappaB, cyclic adenosine 3',5'-monophosphate-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, cyclooxygenase-2, ornithine decarboxylase and vascular endothelial growth factor. Moreover, this is the first study to demonstrate that AcEGCG is a CD34(+) and PKD1 inhibitor in the multistage 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.
authors: Department of Seafood Science, National Kaohsiung Marine University, Kaohsiung 811, Taiwan.
authors: Yi-Shiou
authors: YS
authors: Chiou
authors: Shengmin
authors: S
authors: Sang
authors: Kuang-Hung
authors: KH
authors: Cheng
authors: Chi-Tang
authors: CT
authors: Ho
authors: Ying-Jan
authors: YJ
authors: Wang
authors: Min-Hsiung
authors: MH
authors: Pan
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene; D000085:Acetates / Q000494:pharmacology*; D000818:Animals; D018952:Antigens, CD34 / Q000096:biosynthesis / Q000378:metabolism*; D022762:CCAAT-Enhancer-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D018890:Chemoprevention; D017362:Cyclic AMP Response Element-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D048056:Mitogen-Activated Protein Kinase 9 / Q000378:metabolism; D008940:Mitotic Index; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D009955:Ornithine Decarboxylase / Q000096:biosynthesis; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012878:Skin Neoplasms / Q000188:drug therapy / Q000517:prevention & control*; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000085:Acetates; D018952:Antigens, CD34; D022762:CCAAT-Enhancer-Binding Proteins; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D042461:Vascular Endothelial Growth Factor A; C516941:peracetylated epigallocatechin-3-gallate; D015127:9,10-Dimethyl-1,2-benzanthracene; D002392:Catechin; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D058539:Phosphatidylinositol 3-Kinase; D048056:Mitogen-Activated Protein Kinase 9; C089212:protein kinase D; D051057:Proto-Oncogene Proteins c-akt; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases; D048055:Mitogen-Activated Protein Kinase 8; D048051:p38 Mitogen-Activated Protein Kinases; D009955:Ornithine Decarboxylase; D013755:Tetradecanoylphorbol Acetate