title: Curcumin downregulates p38 MAPK-dependent X-ray repair cross-complement group 1 (XRCC1) expression to enhance cisplatin-induced cytotoxicity in human lung cancer cells.
abstract: Cisplatin is a well-studied and widely used chemotherapeutic agent and is effective in the treatment of the advanced human non-small cell lung cancer (NSCLC). Curcumin is a yellow pigment derived from the rhizome of Curcuma longa and has been proved to have antioxidant and antitumor properties. XRCC1 is an important scaffold protein involved in base excision repair and plays an important role in the development of lung cancer. In this study, we characterize the role of curcumin in the cytotoxicity, p38 MAPK activation, and XRCC1 expression affected by cisplatin in NSCLC cells. We show that curcumin enhanced the cytotoxicity induced by cisplatin in two NSCLC cells, A549 and H1703. Treatment with cisplatin alone increased XRCC1 mRNA and protein expression through p38 MAPK activation. Moreover, SB2023580 (p38 inhibitor) decreased the XRCC1 mRNA and protein stability upon cisplatin treatment. Knockdown of XRCC1 in NSCLC cells by transfection of XRCC1 siRNA or inactivation of p38 MAPK resulted in enhancing the cytotoxicity and cell growth inhibition induced by cisplatin. Curcumin inhibited the expression of XRCC1 in cisplatin-exposed NSCLC cells. Furthermore, transfection with constitutive active MKK6 or HA-p38 MAPK vectors rescued the XRCC1 protein level and also the cell survival suppressed by cisplatin and curcumin combination in A549 and H1703 cells. These findings suggested that the downregulation of XRCC1 expression by curcumin can enhance the chemosensitivity of cisplatin in NSCLC cells.
authors.affiliation: Department of Pathology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan.|Chang Gung University of Science and Technology, Chiayi, Taiwan.
authors.forename: Chun-Liang
authors.initials: CL
authors.lastname: Tung
authors.affiliation: Department of Pathology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan.
authors.forename: Yi-Jun
authors.initials: YJ
authors.lastname: Jian
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, 300 Syuefu Road, Chiayi, 600, Taiwan.
authors.forename: Tai-Jing
authors.initials: TJ
authors.lastname: Wang
authors.affiliation: Department of Biochemical Science and Technology, National Chiayi University, 300 Syuefu Road, Chiayi, 600, Taiwan.
authors.forename: Wen-Ching
authors.initials: WC
authors.lastname: Chen
authors.affiliation: Department of Biochemical Science and Technology, National Chiayi University, 300 Syuefu Road, Chiayi, 600, Taiwan.
authors.forename: Hao-Yu
authors.initials: HY
authors.lastname: Zheng
authors.affiliation: Department of Biochemical Science and Technology, National Chiayi University, 300 Syuefu Road, Chiayi, 600, Taiwan.
authors.forename: Po-Yuan
authors.initials: PY
authors.lastname: Chang
authors.affiliation: Department of Pathology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan.
authors.forename: Kai-Sheng
authors.initials: KS
authors.lastname: Liao
authors.affiliation: Department of Biochemical Science and Technology, National Chiayi University, 300 Syuefu Road, Chiayi, 600, Taiwan. linyw@mail.ncyu.edu.tw.
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; D002945:Cisplatin / Q000494:pharmacology*; D003474:Curcumin / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004789:Enzyme Activation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D048669:MAP Kinase Kinase 6 / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D000076105:X-ray Repair Cross Complementing Protein 1; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human; D048051:p38 Mitogen-Activated Protein Kinases; D048669:MAP Kinase Kinase 6; D003474:Curcumin; D002945:Cisplatin
keywords: Cisplatin; Curcumin; Non-small cell lung cancer; XRCC1; p38 MAPK