Back to Search
Start Over
MEK1/2 inhibition enhances the radiosensitivity of cancer cells by downregulating survival and growth signals mediated by EGFR ligands.
- Source :
-
International journal of oncology [Int J Oncol] 2013 Jun; Vol. 42 (6), pp. 2028-36. Date of Electronic Publication: 2013 Apr 10. - Publication Year :
- 2013
-
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.
- Subjects :
- ADAM Proteins metabolism
ADAM17 Protein
Animals
Cell Line, Tumor drug effects
Cell Line, Tumor radiation effects
Cell Survival drug effects
Cell Survival radiation effects
Humans
Ligands
Mice
Mice, Nude
Mutation
Neoplasms metabolism
Neoplasms pathology
Protein Kinase Inhibitors pharmacology
Proto-Oncogene Proteins genetics
Proto-Oncogene Proteins p21(ras)
Radiation Tolerance drug effects
Radiation, Ionizing
Signal Transduction drug effects
Transforming Growth Factor alpha metabolism
Transforming Growth Factor alpha pharmacology
Xenograft Model Antitumor Assays
ras Proteins genetics
Benzimidazoles pharmacology
ErbB Receptors metabolism
MAP Kinase Kinase 1 antagonists & inhibitors
MAP Kinase Kinase 2 antagonists & inhibitors
Neoplasms radiotherapy
Radiation-Sensitizing Agents pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1791-2423
- Volume :
- 42
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- International journal of oncology
- Publication Type :
- Academic Journal
- Accession number :
- 23588995
- Full Text :
- https://doi.org/10.3892/ijo.2013.1890