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Research Articles: Therapeutics, Targets, and Development

Requirement of hypoxia-inducible factor-1 down-regulation in mediating the antitumor activity of the anti–epidermal growth factor receptor monoclonal antibody cetuximab

¹ Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center; and ² Department of Neurology, Baylor College of Medicine, Houston, Texas

Requests for reprints: Zhen Fan, Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Unit 036, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-745-3560; Fax: 713-745-3562. E-mail: zfan{at}mdanderson.org

Abstract

We tested our novel hypothesis that down-regulation of hypoxia-inducible factor-1 (HIF-1), the regulated subunit of HIF-1 transcription factor that controls gene expression involved in key functional properties of cancer cells (including metabolism, survival, proliferation, invasion, angiogenesis, and metastasis), contributes to a major antitumor mechanism of cetuximab, an approved therapeutic monoclonal antibody that blocks activation of the epidermal growth factor receptor. We showed that cetuximab treatment down-regulates HIF-1 levels by inhibiting synthesis of HIF-1 rather than by enhancing degradation of the protein. Inhibition of HIF-1 protein synthesis was dependent on effective inhibition of the phosphoinositide-3 kinase (PI3K)/Akt pathway by cetuximab, because the inhibition was prevented in cells transfected with a constitutively active PI3K or a constitutively active Akt but not in cells with a constitutively active MEK. Overexpression of HIF-1 conferred cellular resistance to cetuximab-induced apoptosis and inhibition of vascular endothelial growth factor production in sensitive cancer cell models, and expression knockdown of HIF-1 by RNA interference substantially restored cellular sensitivity to the cetuximab-mediated antitumor activities in experimental resistant cell models created by transfection of an oncogenic Ras gene (G12V) or by concurrent treatment of the cells with insulin-like growth factor-I. In summary, our data show that cetuximab decreases HIF-1 protein synthesis through inhibition of a PI3K-dependent pathway and that an effective down-regulation of HIF-1 is required for maximal therapeutic effects of cetuximab in cancer cells. [Mol Cancer Ther 2008;7(5):1207–17]

Grant support: Bristol-Myers Squibb, Breast Cancer Research Foundation, and National Cancer Institute Cancer Center Support Grant P30 CA16672.

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.

Received 10/12/07; revised 2/ 1/08; accepted 3/ 4/08.