MEK1/2 inhibition enhances the radiosensitivity of cancer cells by downregulating survival and growth signals mediated by EGFR ligands
| Autor: | Mary Ellen Urick, Paul D. Smith, Naamit Kurshan, Hiroaki Asano, William P Shield, Eun Joo Chung, Bradley Scroggins, Deborah Citrin, Jeffrey Burkeen |
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| Rok vydání: | 2013 |
| Předmět: |
MAPK/ERK pathway
Radiation-Sensitizing Agents Cancer Research TGF alpha Cell Survival MAP Kinase Kinase 2 MAP Kinase Kinase 1 Mice Nude ADAM17 Protein Biology Ligands AZD6244 Radiation Tolerance Proto-Oncogene Proteins p21(ras) Mice Cell Line Tumor Neoplasms Proto-Oncogene Proteins Radiation Ionizing Animals Humans Autocrine signalling Protein Kinase Inhibitors selumetinib Oncogene Articles Transforming Growth Factor alpha Xenograft Model Antitumor Assays Molecular biology transforming growth factor-α ErbB Receptors radiation ADAM Proteins Oncology Mutation Cancer cell ras Proteins Selumetinib Cancer research Benzimidazoles Signal transduction Signal Transduction Ras |
| Zdroj: | International Journal of Oncology |
| ISSN: | 1791-2423 1019-6439 |
| DOI: | 10.3892/ijo.2013.1890 |
| Popis: | 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 check-point 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. |
| Databáze: | OpenAIRE |
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