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/S F) is a multifunctional cytokine that stimulates tumor cell invasion and an giogenesis. We recently reported that HGF/SF protects epithelial and carcin oma cells against cytotoxicity from DNA-damaging agents and that HGF/SF-med iated cytoprotection was associated with up-regulation of the anti-apoptoti c protein Bcl-X-L in cells exposed to adriamycin, We now; report that in ad dition to blocking apoptosis, HGF/SF markedly enhances the repair of DNA st rand breaks caused by adriamycin or gamma radiation. Constitutive expressio n of Bcl-X-L in MDA-MB-453 breast cancer cells not only simulated the HGF/S F-mediated chemoradioresistance, but also enhanced the repair of DNA strand breaks, The ability of HGF/SF to induce both chemoresistance and DNA repai r was inhibited by wortmannin, suggesting that these activities of HGF/SF a re due, in part, to a phosphatidylinositol-3'-kinase (PI3K) dependent signa ling pathway. Consistent with this finding, HGF/SF induced the phosphorylat ion of c-Akt (protein kinase-B), a PI3K substrate implicated in apoptosis i nhibition; and an expression vector encoding a dominant negative kinase ina ctive Akt partially but significantly inhibited HGF/SF-mediated cell protec tion and DNA repair. These findings suggest that HGF/SF activates a cell su rvival 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.