Proteomic investigating the cooperative lethal effect of EGFR and MDM2 inhibitors on ovarian carcinoma
Journal
Archives of Biochemistry and Biophysics
Journal Volume
647
Pages
10-32
Date Issued
2018
Author(s)
Chang S.-J.
Liao E.-C.
Yeo H.-Y.
Chen H.-Y.
Tsai Y.-T.
Wei Y.-S.
Chen Y.-J.
Wang Y.-S.
Li J.-M.
Shih C.-C.
Chan C.-H.
Chou H.-C.
Chuang Y.-J.
Chan H.-L.
Abstract
With the concept of precision medicine, combining multiple molecular-targeting therapies has brought new approaches to current cancer treatments. Malfunction of the tumor suppressor protein, p53 is a universal hallmark in human cancers. Under normal conditions, p53 is degraded through an ubiquitin-proteosome pathway regulated by its negative regulator, MDM2. In contrast, cellular stress such as DNA damage will activate p53 to carry out DNA repair, cell cycle arrest, and apoptosis. In this study, we focused on ovarian carcinoma with high EGFR and MDM2 overexpression rate. We assessed the effects of combined inhibition by MDM2 (JNJ-26854165) and EGFR (gefitinib) inhibitors on various ovarian cell lines to determine the importance of these two molecular targets on cell proliferation. We then used a proteomic strategy to investigate the relationship between MDM2 and EGFR inhibition to explore the underlying mechanisms of how their combined signaling blockades work together to exert cooperative inhibition. Our results demonstrated that all four cell lines were sensitive to both individual and combined, MDM2 and EGFR inhibition. The proteomic analysis also showed that gefitinib/JNJ-treated CAOV3 cells exhibited downregulation of proteins involved in nucleotide biosynthesis such as nucleoside diphosphate kinase B (NME2). In conclusion, our study showed that the combined treatment with JNJ and gefitinib exerted synergistic inhibition on cell proliferation, thereby suggesting the potential application of combining MDM2 inhibitors with EGFR inhibitors for enhancing efficacy in ovarian cancer treatment. ? 2018 Elsevier Inc.
Subjects
DIGE; EGFR; MDM2; Proteomics
SDGs
Other Subjects
actin; actin, cytoplasmic 1; actin, cytoplasmic 2; acyl coenzyme A; adenine phosphoribosyltransferase; aldehyde reductase; alpha enolase; cofilin 1; elongation factor 1beta; ezrin; gefitinib; glyceraldehyde 3 phosphate dehydrogenase; glycerophosphoinositol inositolphosphodiesterase; inorganic pyrophosphatase; isocitric acid; lipocortin 1; malate dehydrogenase; nucleoside diphosphate kinase; nucleoside diphosphate kinase B; oxidoreductase; phosphoglycerate kinase; phosphoglycerate mutase; phosphoglycerate mutase 1; protein disulfide isomerase; protein MDM2; pyruvate kinase; pyruvate kinase PKM; retinoblastoma binding protein 4; serdemetan; stathmin; unclassified drug; antineoplastic agent; EGFR protein, human; epidermal growth factor receptor; gefitinib; MDM2 protein, human; protein MDM2; proteome; serdemetan; tryptamine derivative; Article; Caov-3 cell line; cell proliferation; cell survival; cell viability; comparative study; controlled study; down regulation; drug efficacy; drug potentiation; enzyme inhibition; growth inhibition; HEY A8 cell line; IC50; image analysis; immunoblotting; matrix assisted laser desorption ionization time of flight mass spectrometry; ovary carcinoma; OVCAR-3 cell line; priority journal; protein expression; proteomics; two dimensional difference gel electrophoresis; antagonists and inhibitors; apoptosis; drug effect; female; human; metabolism; ovary tumor; pathology; proteomics; tumor cell line; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Cell Proliferation; Drug Synergism; ErbB Receptors; Female; Gefitinib; Humans; Ovarian Neoplasms; Proteome; Proteomics; Proto-Oncogene Proteins c-mdm2; Tryptamines
Publisher
Academic Press Inc.
Type
journal article