The cytokine hepatocyte growth factor/scatter factor inhibits apoptosis and enhances DNA repair by a common mechanism involving signaling through phosphatidyl inositol 3′ kinase

Scatter factor (SF) [aka, hepatocyte growth factor (HGF)] (designated HGF/SF) is a multifunctional cytokine that stimulates tumor cell invasion and angiogenesis. We recently reported that HGF/SF protects epithelial and carcinoma cells against cytotoxicity from DNA-damaging agents and that HGF/SF-mediated cytoprotection was associated with up-regulation of the anti-apoptotic protein Bcl-X-L in cells exposed to adriamycin, We now; report that in addition to blocking apoptosis, HGF/SF markedly enhances the repair of DNA strand breaks caused by adriamycin or gamma radiation. Constitutive expression of Bcl-X-L in MDA-MB-453 breast cancer cells not only simulated the HGF/SF-mediated chemoradioresistance, but also enhanced the repair of DNA strand breaks, The ability of HGF/SF to induce both chemoresistance and DNA repair was inhibited by wortmannin, suggesting that these activities of HGF/SF are due, in part, to a phosphatidylinositol-3'-kinase (PI3K) dependent signaling pathway. Consistent with this finding, HGF/SF induced the phosphorylation of c-Akt (protein kinase-B), a PI3K substrate implicated in apoptosis inhibition; and an expression vector encoding a dominant negative kinase inactive Akt partially but significantly inhibited HGF/SF-mediated cell protection and DNA repair. These findings suggest that HGF/SF activates a cell survival and DNA repair pathway;ay that involves signaling through PI3K and c-Akt and stabilization of the expression of Bcl-X-L and they implicate Bcl-X-L in the DNA repair process.