title: Scatter factor/hepatocyte growth factor protects against cytotoxic death in human glioblastoma via phosphatidylinositol 3-kinase- and AKT-dependent pathways.
abstract: 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.
authors.affiliation: Johns Hopkins Oncology Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: D C
authors.initials: DC
authors.lastname: Bowers
authors.forename: S
authors.initials: S
authors.lastname: Fan
authors.forename: K A
authors.initials: KA
authors.lastname: Walter
authors.forename: R
authors.initials: R
authors.lastname: Abounader
authors.forename: J A
authors.initials: JA
authors.lastname: Williams
authors.forename: E M
authors.initials: EM
authors.lastname: Rosen
authors.forename: J
authors.initials: J
authors.lastname: Laterra
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D015870:Gene Expression; D018014:Gene Transfer Techniques; D005909:Glioblastoma / Q000201:enzymology / Q000473:pathology*; D018316:Gliosarcoma / Q000201:enzymology / Q000473:pathology; D017228:Hepatocyte Growth Factor / Q000494:pharmacology* / Q000502:physiology; D006801:Humans; D008297:Male; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D016337:RNA, Catalytic / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D011994:Recombinant Proteins / Q000494:pharmacology; D017412:Ribonucleoprotein, U1 Small Nuclear / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D014407:Tumor Cells, Cultured
chemical_list: D017228:Hepatocyte Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019859:Proto-Oncogene Proteins c-met; D016337:RNA, Catalytic; D011994:Recombinant Proteins; D017412:Ribonucleoprotein, U1 Small Nuclear; C494918:AKT1 protein, human; C494920:Akt1 protein, rat