Resveratrol Enhances Etoposide-Induced Cytotoxicity through Down-Regulating ERK1/2 and AKT-Mediated X-ray Repair Cross-Complement Group 1 (XRCC1) Protein Expression in Human Non-Small-Cell Lung Cancer Cells
Journal
Basic and Clinical Pharmacology and Toxicology
Journal Volume
117
Journal Issue
6
Pages
383-391
Date Issued
2015
Author(s)
Abstract
Etoposide (VP-16), a topoisomerase II inhibitor, is an effective anti-cancer drug used for the treatment of non-small-cell lung cancer (NSCLC). Resveratrol is a naturally occurring polyphenolic compound that has been proved to have anti-cancer activity. XRCC1 is an important scaffold protein involved in base excision repair that is regulated by ERK1/2 and AKT signals and plays an important role in the development of lung cancer. However, the role of ERK1/2 and AKT-mediated XRCC1 expression in etoposide treatment alone or combined with resveratrol-induced cytotoxicity in NSCLC cells has not been identified. In this study, etoposide treatment increased XRCC1 mRNA and protein expression through AKT and ERK1/2 activation in two NSCLC cells, H1703 and H1975. Knockdown of XRCC1 in NSCLC cells by transfection of XRCC1 siRNA or inactivation of ERK1/2 and AKT resulted in enhancing cytotoxicity and cell growth inhibition induced by etoposide. Resveratrol inhibited the expression of XRCC1 and enhanced the etoposide-induced cell death and anti-proliferation effect in NSCLC cells. Furthermore, transfection with constitutive active MKK1 or AKT vectors could rescue the XRCC1 protein level and also the cell survival suppressed by co-treatment with etoposide and resveratrol. These findings suggested that down-regulation of XRCC1 expression by resveratrol can enhance the chemosensitivity of etoposide in NSCLC cells. ? 2015 Nordic Association for the Publication of BCPT.
SDGs
Other Subjects
1,4 diamino 1,4 bis(2 aminophenylthio) 2,3 dicyanobutadiene; 2 morpholino 8 phenylchromone; dactinomycin; etoposide; mitogen activated protein kinase 1; mitogen activated protein kinase 3; protein kinase B; resveratrol; XRCC1 protein; antineoplastic agent; DNA binding protein; etoposide; MAP2K1 protein, human; MAPK1 protein, human; mitogen activated protein kinase 1; mitogen activated protein kinase 3; mitogen activated protein kinase kinase 1; protein kinase B; resveratrol; stilbene derivative; X-ray repair cross complementing protein 1; antineoplastic activity; antiproliferative activity; Article; cancer cell; cancer inhibition; cell death; cell proliferation; cell survival; controlled study; down regulation; drug cytotoxicity; enzyme activation; enzyme activity; enzyme inactivation; gene expression; genetic transfection; human; human cell; non small cell lung cancer; priority journal; protein expression; real time polymerase chain reaction; RNA synthesis; upregulation; Western blotting; Carcinoma, Non-Small-Cell Lung; dose response; down regulation; drug effects; drug resistance; enzymology; gene expression regulation; genetics; Lung Neoplasms; metabolism; pathology; phosphorylation; RNA interference; signal transduction; time factor; tumor cell line; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Cell Survival; DNA-Binding Proteins; Dose-Response Relationship, Drug; Down-Regulation; Drug Resistance, Neoplasm; Etoposide; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; MAP Kinase Kinase 1; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Phosphorylation; Proto-Oncogene Proteins c-akt; RNA Interference; Signal Transduction; Stilbenes; Time Factors; Transfection
Publisher
Blackwell Publishing Ltd
Type
journal article