MEK1/2 inhibition enhances the radiosensitivity of cancer cells by downregulating survival and growth signals mediated by EGFR ligands

  • Authors:
    • Eun Joo Chung
    • Mary Ellen Urick
    • Naamit Kurshan
    • William Shield
    • Hiroaki Asano
    • Paul D. Smith
    • Bradley S. Scroggins
    • Jeffrey Burkeen
    • Deborah E. Citrin
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  • Published online on: April 10, 2013     https://doi.org/10.3892/ijo.2013.1890
  • Pages: 2028-2036
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Abstract

The inhibition of the Ras/mitogen-activated protein kinase (Ras/MAPK) pathway through the suppression of mutated Ras or MAPK/extracellular signal-regulated kinase 1/2 (MEK1/2) has been shown to sensitize tumor cells to ionizing radiation (IR). The molecular mechanisms of this sensitization however, are not yet fully understood. In this study, we investigated the role of transforming growth factor-α (TGF-α) in the radiosensitizing effects of selumetinib, a selective inhibitor of MEK1/2. The expression of epidermal growth factor receptor (EGFR) ligands was assessed by ELISA in both Ras wild-type and Ras mutant cells that were exposed to radiation with or without selumetinib. The effects of selumetinib on the TGF-α/EGFR signaling cascade in response to radiation were examined by western blot analysis, clonogenic assay and by determing the yield of mitotic catastrophe. The treatment of cells with selumetinib reduced the basal and IR-induced secretion of TGF-α in both Ras wild-type and Ras mutant cell lines in vitro and in vivo. The reduction of TGF-α secretion was accompanied with a reduction in phosphorylated tumor necrosis factor-α converting enzyme (TACE) in the cells treated with selumetinib with or without IR. The treatment of cells with selumetinib with or without IR inhibited the phosphorylation of EGFR and checkpoint kinase 2 (Chk2), and reduced the expression of survivin. Supplementation with exogenous TGF-α partially rescued the selumetinib-treated cells from IR-induced cell death, restored EGFR and Chk2 phosphorylation and increased survivin expression. These data suggest that the inhibition of MEK1/2 with selumetinib may provide a mechanism to sensitize tumor cells to IR in a fashion that prevents the activation of the TGF-α autocrine loop following IR.
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June 2013
Volume 42 Issue 6

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Chung EJ, Urick ME, Kurshan N, Shield W, Asano H, Smith PD, Scroggins BS, Burkeen J and Citrin DE: MEK1/2 inhibition enhances the radiosensitivity of cancer cells by downregulating survival and growth signals mediated by EGFR ligands. Int J Oncol 42: 2028-2036, 2013
APA
Chung, E.J., Urick, M.E., Kurshan, N., Shield , W., Asano, H., Smith, P.D. ... Citrin, D.E. (2013). MEK1/2 inhibition enhances the radiosensitivity of cancer cells by downregulating survival and growth signals mediated by EGFR ligands. International Journal of Oncology, 42, 2028-2036. https://doi.org/10.3892/ijo.2013.1890
MLA
Chung, E. J., Urick, M. E., Kurshan, N., Shield , W., Asano, H., Smith, P. D., Scroggins, B. S., Burkeen, J., Citrin, D. E."MEK1/2 inhibition enhances the radiosensitivity of cancer cells by downregulating survival and growth signals mediated by EGFR ligands". International Journal of Oncology 42.6 (2013): 2028-2036.
Chicago
Chung, E. J., Urick, M. E., Kurshan, N., Shield , W., Asano, H., Smith, P. D., Scroggins, B. S., Burkeen, J., Citrin, D. E."MEK1/2 inhibition enhances the radiosensitivity of cancer cells by downregulating survival and growth signals mediated by EGFR ligands". International Journal of Oncology 42, no. 6 (2013): 2028-2036. https://doi.org/10.3892/ijo.2013.1890