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[Cancer Research 60, 4277-4283, August 1, 2000]
© 2000 American Association for Cancer Research

Tumor Biology

Scatter Factor/Hepatocyte Growth Factor Protects against Cytotoxic Death in Human Glioblastoma via Phosphatidylinositol 3-Kinase- and AKT-dependent Pathways1

Daniel C. Bowers, Saijun Fan, Kevin A. Walter, Roger Abounader, Jeffery A. Williams, Eliot M. Rosen and John Laterra2

Johns Hopkins Oncology Center [D. C. B., J. A. W., J. L.] and the Departments of Pediatrics [D. C. B.], Neurology [R. A., J. L.], Neuroscience [J. L.], and Neurosurgery [K. A. W., J. A. W.], The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287; Kennedy Krieger Research Institute, Baltimore, Maryland 21205 [R. A., J. L.]; and the Department of Radiation Oncology, Long Island Jewish Medical Center, New Hyde Park, New York 11042 [S. F., E. M. R.]

We have shown recently that the multifunctional growth factor, scatter factor/hepatocyte growth factor (SF/HGF), and its receptor c-met enhance the malignancy of human glioblastoma through an autocrine stimulatory loop (R. Abounader et al., J. Natl. Cancer Inst., 91: 1548–1556, 1999). This report examines the effects of SF/HGF:c-met signaling on human glioma cell responses to DNA-damaging agents. Pretreating U373 human glioblastoma cells with recombinant SF/HGF partially abrogated their cytotoxic responses to gamma irradiation, cisplatin, camptothecin, Adriamycin, and Taxol in vitro. This cytoprotective effect of SF/HGF occurred at least in part through an inhibition of apoptosis, as evidenced by diminished terminal deoxynucleotidyl transferase-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 cell death caused by DNA-damaging agents, demonstrating a requirement for c-met receptor function. Phosphorylation of the cell survival-promoting kinase Akt (protein kinase B) resulted from SF/HGF treatment of U373 cells, and both Akt phosphorylation and cell survival induced by SF/HGF were inhibited by 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-negative 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 activation by SF/HGF protects certain glioblastoma cells from DNA-damaging agents by activating phosphoinositol 3-kinase-dependent and Akt-dependent antiapoptotic pathways.




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