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  • Original Paper
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The antiepidermal growth factor receptor monoclonal antibody cetuximab/C225 reduces hypoxia-inducible factor-1 alpha, leading to transcriptional inhibition of vascular endothelial growth factor expression

Oncogene volume 24, pages 4433–4441 (2005)Cite this article

Abstract

We have previously shown that the antiepidermal growth factor receptor monoclonal antibody cetuximab (C225; Erbitux), which was recently approved for the treatment of metastatic colorectal cancer, has antiangiogenic properties, inhibiting vascular endothelial growth factor (VEGF) secretion in culture and in animal models. Here, we have furthered the study by demonstrating that cetuximab reduces cellular levels of hypoxia-inducible factor-1 alpha (HIF-1α), a transcriptional regulator of VEGF expression, in A431 epidermoid carcinoma cells under both normoxic and hypoxic culture conditions. Expression of a constitutively active Ras in A431 cells rendered cellular resistance to the cetuximab-mediated reduction of the HIF-1α level. Cell lines with naturally occurring phosphatase and tensin homologue deleted on chromosome 10 mutations or deletions were also resistant to cetuximab-mediated reduction of the HIF-1α level. Pharmacologic inhibition of phosphatidylinositol 3-kinase with LY294002 reduced the HIF-1α level in both normoxic and hypoxic A431 cells, whereas inhibition of the mitogen-activated protein kinase kinase by PD98059 reduced the level of HIF-1α only in normoxic A431 cells. In addition, cetuximab reduced the cellular level of HIF-1α in the presence of a proteasome inhibitor, lactacystin, indicating that cetuximab acts mainly at the level of protein synthesis. The reduction of HIF-1α in response to cetuximab treatment was accompanied by transcriptional inhibition of VEGF expression, measured by a luciferase assay in A431 cells transfected with a vector containing the VEGF hypoxia response element. Taken together, our results indicate that the previously demonstrated inhibition of VEGF by cetuximab occurs at the level of transcription in response to a reduced level of HIF-1α and justify further testing of therapeutic strategies that combine cetuximab with approaches inhibiting the function of VEGF or the VEGF receptor.

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Acknowledgements

We thank Drs Erwin G Van Meir and Dawn E Post (Department of Neurosurgery, Winship Cancer Institute, Emory University, Atlanta, GA, USA) for providing the pBI-GL-V6L construct and Mr David Galloway (Department of Scientific Publications, MD Anderson Cancer Center, Houston, TX, USA) for editorial assistance. This work was supported in part by a generous grant from the Breast Cancer Research Foundation (New York, NY, USA).

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  1. Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Unit 036, 1515 Holcombe Blvd., Houston, TX, 77030, USA

    Rodney B Luwor, Yang Lu, Xinqun Li, John Mendelsohn & Zhen Fan

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Luwor, R., Lu, Y., Li, X. et al. The antiepidermal growth factor receptor monoclonal antibody cetuximab/C225 reduces hypoxia-inducible factor-1 alpha, leading to transcriptional inhibition of vascular endothelial growth factor expression. Oncogene 24, 4433–4441 (2005). https://doi.org/10.1038/sj.onc.1208625

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