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Role of NF-κB signaling in hepatocyte growth factor/scatter factor-mediated cell protection

Oncogene volume 24, pages 1749–1766 (2005)Cite this article

Abstract

The cytokine scatter factor/hepatocyte growth factor (HGF/SF) protects epithelial, carcinoma, and other cell types against cytotoxicity and apoptosis induced by DNA-damaging agents such as ionizing radiation and adriamycin (ADR, a topoisomerase IIα inhibitor). We investigated the role of nuclear factor kappa B (NF-κB) signaling in HGF/SF-mediated protection of human prostate cancer (DU-145) and Madin–Darby canine kidney (MDCK) epithelial cells against ADR. HGF/SF caused the rapid nuclear translocation of the p65 (RelA) subunit of NF-κB associated with the transient loss of the inhibitory subunit IκB-α. Exposure to HGF/SF caused the activation of an NF-κB luciferase reporter that was blocked or attenuated by the expression of a mutant ‘super-repressor’ IκB-α. Electrophoretic mobility shift assay supershift assays revealed that HGF/SF treatment induced the transient binding of various NF-κB family proteins (p65, p50, c-Rel, and RelB) with radiolabeled NF-κB-binding oligonucleotides. The HGF/SF-mediated protection of DU-145 and MDCK cells against ADR (demonstrated using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays) was abrogated by the IκB-α super-repressor. The ability of HGF/SF to activate NF-κB signaling was dependent on c-Akt → Pak1 (p21-associated kinase-1) signaling (with Pak1 downstream of c-Akt) and was inhibited by the tumor suppressor PTEN (phosphatase and tensin homolog). Inhibitors of phosphatidylinositol-3′-kinase and Src family kinases significantly inhibited HGF/SF-mediated activation of NF-κB, while inhibitors of MEK, protein kinase C, and p70 S6 kinase had a modest effect or no effect on NF-κB activity. HGF/SF induced the expression of several known NF-κB target genes (cIAP-1 (cellular inhibitor of apoptosis-1), cIAP-2, and TRAF-2 (TNF receptor-associated factor-2)) in an NF-κB-dependent manner; HGF/SF blocked the inhibition of expression of these genes by ADR. Experimental manipulation of expression of these genes suggests that they (particularly TRAF-2 and cIAP-2) contribute to the protection against ADR by HGF/SF. These findings suggest that HGF/SF activates NF-κB through a c-Akt → Pak1 signaling pathway that is also dependent on Src, and that NF-κB contributes to HGF/SF-mediated protection against ADR.

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Acknowledgements

This work was supported, in part, USPHS grants RO1-ES09169 (EMR), RO1-NS43987 (JJL/ EMR), RO1-CA80000 (EMR), RO1-CA82599 (EMR), and R21AA13122 (SF).

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Authors and Affiliations

  1. Department of Oncology, Lombardi Cancer Center/Georgetown University, 3970 Reservoir Road, NW, Box 571469, Washington, DC, 20057-1469, USA

    Saijun Fan, Qinghui Meng, Richard G Pestell & Eliot M Rosen

  2. Department of Radiation Oncology, Long Island Jewish Medical Center, North Shore-Long Island Jewish Research Institute, 270-05 76th Avenue, New Hyde Park, NY, 11040, USA

    Min Gao & Itzhak D Goldberg

  3. The Kennedy Krieger Institute, Johns Hopkins University School of Medicine, 707 N. Broadway, Baltimore, MD, 21205, USA

    John J Laterra

  4. North Shore-Long Island Jewish Health System, North Shore-Long Island Jewish Research Institute, 350 Community Drive, Manhasset, NY, 11030, USA

    Marc H Symons, Sal Coniglio & Itzhak D Goldberg

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  1. Saijun Fan
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Correspondence to Eliot M Rosen.

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Fan, S., Gao, M., Meng, Q. et al. Role of NF-κB signaling in hepatocyte growth factor/scatter factor-mediated cell protection. Oncogene 24, 1749–1766 (2005). https://doi.org/10.1038/sj.onc.1208327

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