title: Enhancement of mitomycin C-induced cytotoxicity by curcumin results from down-regulation of MKK1/2-ERK1/2-mediated thymidine phosphorylase expression.
abstract: Curcumin (diferuloylmethane), a phenolic compound obtained from the rhizome of Curcuma longa, has been found to inhibit cell proliferation in various human cancer cell lines, including non-small cell lung cancer (NSCLC). Thymidine phosphorylase (TP) is considered an attractive therapeutic target, because increased TP expression can suppress cancer cell death induced by DNA-damaging agents. Mitomycin C (MMC), a chemotherapeutic agent used to treat NSCLC, inhibits tumour growth through DNA cross-linking and breaking. Whether MMC can affect TP expression in NSCLC is unknown. Therefore, in this study, we suggested that curcumin enhances the effects of MMC-mediated cytotoxicity by decreasing TP expression and ERK1/2 activation. Exposure of human NSCLC cell lines H1975 and H1650 to curcumin decreased MMC-elicited phosphorylated MKK1/2-ERK1/2 protein levels. Moreover, curcumin significantly decreased MMC-induced TP protein levels by increasing TP mRNA and protein instability. Enhancement of ERK1/2 activation by constitutively active MKK1/2 (MKK1/2-CA) increased TP protein levels and cell viability in curcumin- and MMC-co-treated cells. In contrast, U0126, a MKK1/2 inhibitor, augmented the cytotoxic effect and the down-regulation of TP by curcumin and MMC. Specific inhibition of TP by siRNA significantly enhanced MMC-induced cell death and cell growth inhibition. Our results suggest that suppression of TP expression or administration of curcumin along with MMC may be a novel lung cancer therapeutic modality in the future.
authors.affiliation: Molecular Oncology Laboratory, Department of Biochemical Science and Technology, National Chiayi University, Chiayi, Taiwan.
authors.forename: Shao-Hsing
authors.initials: SH
authors.lastname: Weng
authors.forename: Min-Shao
authors.initials: MS
authors.lastname: Tsai
authors.forename: Yu-Fan
authors.initials: YF
authors.lastname: Chiu
authors.forename: Ya-Hsun
authors.initials: YH
authors.lastname: Kuo
authors.forename: Huang-Jen
authors.initials: HJ
authors.lastname: Chen
authors.forename: Yun-Wei
authors.initials: YW
authors.lastname: Lin
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D030024:Curcuma / Q000737:chemistry; D003474:Curcumin / Q000008:administration & dosage / Q000302:isolation & purification / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D016685:Mitomycin / Q000008:administration & dosage / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D013939:Thymidine Phosphorylase / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D016685:Mitomycin; D013939:Thymidine Phosphorylase; C482128:MAP2K2 protein, human; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human; D003474:Curcumin