Hepatocyte growth factor/scatter factor inhibits UVB-induced apoptosis of human keratinocytes but not of keratinocyte-derived cell lines via the phosphatidylinositol 3-kinase/AKT pathway.
Acute irreparable UV-induced DNA damage leads to apoptosis of epidermal keratinocytes (KC) and the formation of sunburn cells, whereas less severely damaged cells survive but harbor the potential of tumor formation. Here we report that hepatocyte growth factor/scatter factor (HGF/SF) prevents UVB-induced apoptosis in primary KC cultured in vitro. When we analyzed the signaling pathways initiated by the HGF/SF receptor c-met, we found that the phosphatidylinositol (PI) 3-kinase and its downstream-element AKT and the mitogen-activated protein (MAP) kinase were activated. Inhibition of PI 3-kinase led to a complete abrogation of the anti-apoptotic effect of HGF/SF, whereas blockade of the MAP kinase pathway had no effect. In contrast to the observation with primary KC, HGF/SF could not enhance survival after UVB irradiation of HaCaT and A431 cell lines, despite the fact that in these cells the PI 3-kinase and MAP kinase pathways were also activated by HGF/SF. Cell cycle analysis of KC revealed a G(2)/M arrest after UVB irradiation and a complete loss of proliferating cells. Because HGF/SF in the skin is produced by dermal fibroblasts, our findings suggest that the HGF/SF-mediated rescue of KC from apoptosis represents an important paracrine loop by which UVB-damaged KC can be kept alive to maintain the epidermal barrier function but cannot further proliferate, thereby preventing the induction of epithelial skin tumors.
Mildner
Michael
M
Division of Immunology, Allergy and Infectious Diseases, Department of Dermatology, Vienna Medical School, Währinger Gürtel 18-20, A-1090 Vienna, Austria.
Eckhart
Leopold
L
Lengauer
Barbara
B
Tschachler
Erwin
E
D017209:Apoptosis; D015153:Blotting, Western; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle; D002455:Cell Division; D002460:Cell Line; D002461:Cell Line, Transformed; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D012878:Skin Neoplasms / Q000517:prevention & control; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014466:Ultraviolet Rays
D004791:Enzyme Inhibitors; D017228:Hepatocyte Growth Factor; D019869:Phosphatidylinositol 3-Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases