title: Pemetrexed downregulates ERCC1 expression and enhances cytotoxicity effected by resveratrol in human nonsmall cell lung cancer cells.
abstract: The multitargeted antifolate pemetrexed has demonstrated certain clinical activities against nonsmall cell lung cancer (NSCLC). Resveratrol (3,5,4-trihydroxy-trans-stilbene) is a polyphenol found in grapes and other plants and has great potential as a preventative and therapeutic agent due to its anticarcinogenic activity. The efficacy of adding resveratrol to pemetrexed to prolong the survival of patients with NSCLC still remains unclear. The excision repair cross-complementation 1 (ERCC1) is a DNA repair gene coding 5' endonuclease in nucleotide excision repair and is overexpressed in chemo- or radioresistant carcinomas. In this study, resveratrol (10-50 μM) inhibited cell survival in two NSCLC cells, H520 and H1975. Treatment with resveratrol increased ERCC1 messenger RNA and protein levels in a MKK3/6-p38 MAPK signal activation-dependent manner. Furthermore, blocking p38 MAPK activation by SB202190 or knocking down ERCC1 expression by transfection with small interfering RNA of ERCC1 enhanced the cytotoxicity of resveratrol. Combining resveratrol with pemetrexed resulted in a synergistic cytotoxic effect, accompanied with the reduction of phospho-p38 MAPK and ERCC1 protein levels, and a DNA repair capacity. Expression of constitutively active MKK6 (MKK6E) or HA-p38 MAPK vectors significantly rescued the decreased p38 MAPK activity, and restored ERCC1 protein levels and cell survival in resveratrol and pemetrexed cotreated NSCLC cells. In this study, for the first time, we have demonstrated the synergistic effect of combined treatment with resveratrol and pemetrexed in human NSCLC cells through downregulation of the MKK3/6-p38 MAPK-ERCC1 signal, suggesting a potential benefit of combining resveratrol and pemetrexed to treat lung cancer in the future.
authors.affiliation: Department of Biochemical Science and Technology, National Chiayi University, 300 Syuefu Road, Chiayi, 600, Taiwan.
authors.forename: Ruey-Shyang
authors.initials: RS
authors.lastname: Chen
authors.forename: Jen-Chung
authors.initials: JC
authors.lastname: Ko
authors.forename: Hsien-Chun
authors.initials: HC
authors.lastname: Chiu
authors.forename: Ting-Yu
authors.initials: TY
authors.lastname: Wo
authors.forename: Yi-Jhen
authors.initials: YJ
authors.lastname: Huang
authors.forename: Sheng-Chieh
authors.initials: SC
authors.lastname: Tseng
authors.forename: Huang-Jen
authors.initials: HJ
authors.lastname: Chen
authors.forename: Yu-Ching
authors.initials: YC
authors.lastname: Huang
authors.forename: Yi-Jun
authors.initials: YJ
authors.lastname: Jian
authors.forename: Wei-Ting
authors.initials: WT
authors.lastname: Lee
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 / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004720:Endonucleases / Q000378:metabolism*; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D005971:Glutamates / Q000494:pharmacology*; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D048371:MAP Kinase Kinase 3 / Q000378:metabolism; D048669:MAP Kinase Kinase 6 / Q000378:metabolism; D000068437:Pemetrexed; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects; D013267:Stilbenes / Q000494:pharmacology*; D013997:Time Factors; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D005971:Glutamates; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D013267:Stilbenes; D000068437:Pemetrexed; D006147:Guanine; D048051:p38 Mitogen-Activated Protein Kinases; D048371:MAP Kinase Kinase 3; D048669:MAP Kinase Kinase 6; C482530:MAP2K3 protein, human; C482566:MAP2K6 protein, human; C071447:ERCC1 protein, human; D004720:Endonucleases; D000077185:Resveratrol
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