title: 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.
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.
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital, Hsin-Chu Branch, Taiwan.|Department of Nursing, Yuanpei University, Hsinchu, Taiwan.
authors.forename: Jen-Chung
authors.initials: JC
authors.lastname: Ko
authors.affiliation: Department of Biochemical Science and Technology, National Chiayi University, Chiayi, Taiwan.
authors.forename: Jhan-Jhang
authors.initials: JJ
authors.lastname: Syu
authors.affiliation: Department of Food Science, National Chiayi University, Chiayi, Taiwan.
authors.forename: Jyh-Cheng
authors.initials: JC
authors.lastname: Chen
authors.affiliation: Department of Biochemical Science and Technology, National Chiayi University, Chiayi, Taiwan.
authors.forename: Tai-Jing
authors.initials: TJ
authors.lastname: Wang
authors.affiliation: Department of Biochemical Science and Technology, National Chiayi University, Chiayi, Taiwan.
authors.forename: Po-Yuan
authors.initials: PY
authors.lastname: Chang
authors.affiliation: Department of Biochemical Science and Technology, National Chiayi University, Chiayi, Taiwan.
authors.forename: Chien-Yu
authors.initials: CY
authors.lastname: Chen
authors.affiliation: Department of Biochemical Science and Technology, National Chiayi University, Chiayi, Taiwan.
authors.forename: Yun-Ting
authors.initials: YT
authors.lastname: Jian
authors.affiliation: Department of Biochemical Science and Technology, National Chiayi University, Chiayi, Taiwan.
authors.forename: Yi-Jun
authors.initials: YJ
authors.lastname: Jian
authors.affiliation: Department of Biochemical Science and Technology, National Chiayi University, Chiayi, Taiwan.
authors.forename: Yun-Wei
authors.initials: YW
authors.lastname: Lin
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005047:Etoposide / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D048369:MAP Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects; D013267:Stilbenes / Q000494:pharmacology*; D013997:Time Factors; D014162:Transfection; D000076105:X-ray Repair Cross Complementing Protein 1
chemical_list: D004268:DNA-Binding Proteins; D013267:Stilbenes; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human; D005047:Etoposide; D051057:Proto-Oncogene Proteins c-akt; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D000077185:Resveratrol