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


Authors: Fan, S.; Ma, Y. X.; Wang, J. A.; Yuan, R. Q.; Meng, Q.; Cao, Y.; Laterra, J. J.; Goldberg, I. D.; Rosen, E. M.
Article Title: The cytokine hepatocyte growth factor/scatter factor inhibits apoptosis and enhances DNA repair by a common mechanism involving signaling through phosphatidyl inositol 3' kinase
Abstract: 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 HCF/SF-mediated cell protection and DNA repair. These findings suggest that HGF/SF activates a cell survival and DNA repair pathway 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.
Keywords: signal transduction; protein kinase b; controlled study; human cell; proto-oncogene proteins; doxorubicin; antineoplastic agents; dna repair; apoptosis; breast cancer; cancer cell culture; tumor cells, cultured; chemosensitivity; bcl-x protein; breast neoplasms; brca1 protein; phosphatidylinositol 3 kinase; dose-response relationship, radiation; prostatic neoplasms; scatter factor; cytokine; dna; enzyme phosphorylation; protein-serine-threonine kinases; 1-phosphatidylinositol 3-kinase; proto-oncogene proteins c-akt; radiosensitivity; proto-oncogene proteins c-bcl-2; wortmannin; expression vector; mutagens; gamma radiation; gamma rays; c-met; hgf/sf; hepatocyte growth factor; protein bcl x; hepatocyte growth factor (hgf); humans; human; male; female; priority journal; article; adriamycin (doxorubicin); scatter factor (sf); antimutagenic agents
Journal Title: Oncogene
Volume: 19
Issue: 18
ISSN: 0950-9232
Publisher: Nature Publishing Group  
Date Published: 2000-04-27
Start Page: 2212
End Page: 2223
Language: English
PUBMED: 10822371
PROVIDER: scopus
DOI: 10.1038/sj.onc.1203566
DOI/URL:
Notes: Export Date: 18 November 2015 -- Source: Scopus
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  1. Yijian Cao
    3 Cao