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

Oncogene volume 19, pages 2212–2223 (2000)Cite this article

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-XL 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-XL 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 HGF/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-XL; and they implicate Bcl-XL in the DNA repair process.

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Acknowledgements

Sources of Support: Supported, in part, by research grants from the USPHS [R01-ES09169 (EM Rosen) and RO1-NS/CA32148 (JJ Laterra)], the Elsa U. Pardee Cancer Foundation of Michigan (EM Rosen), and the New York State Department of Health (EM Rosen).

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Authors and Affiliations

  1. Department of Radiation Oncology, Long Island Jewish Medical Center, The Long Island Campus for the Albert Einstein College of Medicine, 270-05 76th Avenue, New Hyde Park, New York, 11040, NY, USA

    Saijun Fan, Yong Xian Ma, Ji-An Wang, Ren-Qi Yuan, Qinghui Meng, Itzhak D Goldberg & Eliot M Rosen

  2. Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center at Mercy Medical Center, 1000 North Village Avenue, Rockville Center, New York, 11570, NY, USA

    Yijan Cao

  3. Department of Neurology, Kennedy Krieger Research Institute and The Johns Hopkins School of Medicine, 707 North Broadway, Baltimore, 21205, Maryland, MD, USA

    John J Laterra

  4. Department of Neuroscience, Kennedy Krieger Research Institute and The Johns Hopkins School of Medicine, 707 North Broadway, Baltimore, 21205, Maryland, MD, USA

    John J Laterra

  5. Department of Oncology, Kennedy Krieger Research Institute and The Johns Hopkins School of Medicine, 707 North Broadway, Baltimore, 21205, Maryland, MD, USA

    John J Laterra

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  1. Saijun Fan
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Fan, S., Ma, Y., Wang, JA. et al. The cytokine hepatocyte growth factor/scatter factor inhibits apoptosis and enhances DNA repair by a common mechanism involving signaling through phosphatidyl inositol 3′ kinase. Oncogene 19, 2212–2223 (2000). https://doi.org/10.1038/sj.onc.1203566

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