title: MEK1/2 inhibition enhances the radiosensitivity of cancer cells by downregulating survival and growth signals mediated by EGFR ligands.
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.
authors.affiliation: Section of Translational Radiation Oncology, Radiation Oncology Branch, National Institutes of Health, Bethesda 20892, MD, USA.
authors.forename: Eun Joo
authors.initials: EJ
authors.lastname: Chung
authors.forename: Mary Ellen
authors.initials: ME
authors.lastname: Urick
authors.forename: Naamit
authors.initials: N
authors.lastname: Kurshan
authors.forename: William
authors.initials: W
authors.lastname: Shield
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Asano
authors.forename: Paul D
authors.initials: PD
authors.lastname: Smith
authors.forename: Bradley S
authors.initials: BS
authors.lastname: Scroggins
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Burkeen
authors.forename: Deborah E
authors.initials: DE
authors.lastname: Citrin
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism; D000072198:ADAM17 Protein; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D045744:Cell Line, Tumor / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors*; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors*; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D011836:Radiation Tolerance / Q000187:drug effects; D011839:Radiation, Ionizing; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D016211:Transforming Growth Factor alpha / Q000378:metabolism / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000235:genetics
chemical_list: C517975:AZD 6244; D001562:Benzimidazoles; C117307:KRAS protein, human; D008024:Ligands; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011838:Radiation-Sensitizing Agents; D016211:Transforming Growth Factor alpha; C482128:MAP2K2 protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins