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Role of epidermal growth factor receptor degradation in gemcitabine-mediated cytotoxicity

Oncogene volume 26, pages 3431–3439 (2007)Cite this article

Abstract

We have recently reported that treatment with gemcitabine, a potent chemotherapeutic agent and radiation sensitizer, stimulates phosphorylation of the epidermal growth factor receptor (EGFR). Because phosphorylation of EGFR is known to precede receptor degradation, we hypothesized that gemcitabine treatment may also result in EGFR degradation. In two human head and neck cancer cell lines, UMSCC-1 and UMSCC-6, we demonstrated an approximately 80% decrease in total EGFR levels at 72 h after a 2-h treatment with 1 μ M gemcitabine. Neither cisplatin nor 5-fluorouracil, which are used to treat head and neck cancer, caused EGFR degradation. EGFR downregulation did not occur at the level of transcription, as assessed by reverse transcription-polymerase chain reaction (RT–PCR), but instead occurred via phosphorylation and ubiquitination of the receptor along a proteosome/lysosome-mediated pathway. Inhibition of EGFR degradation, by either pretreatment with the EGFR tyrosine kinase inhibitor gefitinib or by exposure to the proteosome/lysosome inhibitor MG132, significantly reduced gemcitabine-induced cell death. These results suggest that EGFR degradation may be a novel mechanism for gemcitabine-mediated cell death. These findings also indicate that caution should be exercised when combining gemcitabine with agents that may prevent EGFR degradation, such as EGFR tyrosine kinase inhibitors administered in a suboptimal sequence or proteosome inhibitors.

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Acknowledgements

We thank Avraham Eisbruch, Mats Ljungman, Alnawaz Rehemtulla and Aaron Spalding for helpful discussion and Steven Kronenberg for assistance in making figures. Grant support: NIH through the University of Michigan Head and Neck Specialized Program of Research Excellence grant (1 P50 CA97248) and University of Michigan Cancer Center support grant 5 P30 CA46592.

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Authors and Affiliations

  1. Department of Radiation Oncology, University of Michigan Medical Center, Ann Arbor, MI, USA

    F Y Feng, P Y Chun, C A Lopez, X Li, M A Davis, T S Lawrence & M K Nyati

  2. Department of Pathology, University of Michigan Medical Center, Ann Arbor, MI, USA

    S Varambally, S A Tomlins & A M Chinnaiyan

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  1. F Y Feng
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  2. S Varambally
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Correspondence to M K Nyati.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Feng, F., Varambally, S., Tomlins, S. et al. Role of epidermal growth factor receptor degradation in gemcitabine-mediated cytotoxicity. Oncogene 26, 3431–3439 (2007). https://doi.org/10.1038/sj.onc.1210129

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