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J. Biol. Chem., Vol. 281, Issue 36, 25903-25914, September 8, 2006
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Cross-talk between Epidermal Growth Factor Receptor and Hypoxia-inducible Factor-1
Signal Pathways Increases Resistance to Apoptosis by Up-regulating Survivin Gene Expression*
1
From the
Department of Surgery and Winship Cancer Institute and ¶Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia 30322 and the Mary Babb Randolph Cancer Center, Department of Microbiology, Immunology and Cell Biology, West Virginia University, Morgantown, West Virginia 26506
Although increasing evidence supports a link between epidermal growth factor receptor (EGFR) signaling and resistance to apoptosis, the mechanism by which the EGFR signaling pathway inhibits apoptosis is not well understood. In this study, we found that epidermal growth factor (EGF) stimulation increased the level of expression of the inhibitor of apoptosis protein survivin in breast cancer cells but not in normal mammary epithelial cells. We further demonstrated that activation of survivin gene expression is mediated by oxygen-independent hypoxia-inducible factor (HIF)-1
up-regulation in EGF-treated cancer cells. EGFR signaling activated the phosphoinositide 3-kinase/AKT pathway, subsequently increasing the level of HIF-1 under normoxic conditions. HIF-1 then activated survivin gene transcription through direct binding to the survivin promoter. Furthermore, we found that overexpression of HIF-1 small interfering RNA blocks EGF-induced survivin gene up-regulation and increases apoptosis induced by the chemotherapy drug docetaxel. However, transfection of a plasmid expressing HIF-1 gene activates survivin gene expression and reduces the apoptotic response. Our results demonstrate a novel pathway for EGFR signaling-mediated apoptosis resistance in human cancer cells. Although the role of HIF-1 in regulating cell survival under hypoxic conditions has been studied extensively, our results show that normoxic breast cancer cells utilize cross-talk between EGFR signals and HIF-1 to up-regulate the anti-apoptotic survivin gene, providing a strong rationale for the targeting of HIF-1 as a therapeutic approach for both hypoxic and normoxic tumor cells. Understanding key molecular events in EGFR signaling-induced apoptosis resistance should provide new information for the development of novel therapeutic agents targeting EGFR, HIF-1, and/or survivin.
Received for publication, April 10, 2006 , and in revised form, July 12, 2006.
* This work was supported by NCI, National Institutes of Health Grants R29 CA 80017 and R01 CA95643, an Idea Award of the Department of Defense Breast Cancer Research Program, and the Avon Breast Cancer Research Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 To whom correspondence should be addressed: Dept. of Surgery and Winship Cancer Institute, Emory University School of Medicine, Rm. C-4088, 1365 C Clifton Rd., N.E., Atlanta, GA 30322. Tel.: 404-778-4269; Fax: 404-778-5530; E-mail: Lyang02{at}emory.edu.
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