Scatter factor/hepatocyte growth factor protects against cytotoxic death in human glioblastoma via phosphatidylinositol 3-kinase- and AKT-dependent pathways

We have shown recently that the multifunctional growth factor, scatter fact or/hepatocyte growth factor (SF/HGF), and its receptor c-met enhance the ma lignancy of human glioblastoma through an autocrine stimulatory loop (R. Ab ounader et al., J. Natl. Cancer Inst., 91: 1548-1556, 1999). This report ex amines the effects of SF/HGF:c-met signaling on human glioma cell responses to DNA-damaging agents. Pretreating U373 human glioblastoma cells with rec ombinant SF/HGF partially abrogated their cytotoxic responses to gamma irra diation, cisplatin, camptothecin, Adriamycin, and Taxol in vitro. This cyto protective effect of SF/HGF occurred at least in part through an inhibition of apoptosis, as evidenced by diminished terminal deoxynucleotidyl transfe rase-mediated dUTP nick-end labeling index and reduced DNA laddering. Anti- c-met U1/ribozyme gene transfer inhibited the ability of SF/HGF to protect against single-strand DNA breakage, DNA fragmentation, and glioblastoma cel l death caused by DNA-damaging agents, demonstrating a requirement for c-me t receptor function. Phosphorylation of the cell survival-promoting kinase Akt (protein kinase B) resulted from SF/HGF treatment of U373 cells, and bo th Akt phosphorylation and cell survival induced by SF/HGF were inhibited b y phosphatidylinositol 3-kinase inhibitors but not by inhibitors of mitogen -activated protein kinase kinase or protein kinase C. Cytoprotection by SF/ HGF in vitro was also inhibited by transient expression of dominant-negativ e Akt. Transgenic SF/HGF expression by intracranial 9L gliosarcomas reduced tumor cell sensitivity to gamma irradiation, confirming the cytoprotective effect of SF/HGF in vivo. These findings demonstrate that c-met receptor a ctivation by SF/HGF protects certain glioblastoma cells from DNA-damaging a gents by activating phosphoinositol 3-kinase-dependent and Akt-dependent an tiapoptotic pathways.