Molecular Oncology Laboratory, Department of Biochemical Science and Technology, National Chiayi University, Chiayi, Taiwan.
Mol Pharmacol. 2011 Jul;80(1):136-46. doi: 10.1124/mol.111.071316. Epub 2011 Apr 14.
Curcumin (diferuloylmethane), a phenolic compound obtained from the rhizome of Curcuma longa, is known to have antiproliferative and antitumor properties. Thymidine phosphorylase (TP), an enzyme of the pyrimidine salvage pathway, is considered an attractive therapeutic target, and its expression could suppress cancer cell death induced by DNA damage agents. Excision repair cross-complementary 1 (ERCC1) is a protein involved the process of nucleotide excision repair. The ERCC1 gene is expressed at high levels in cancers and has been associated with resistance to platinum-based chemotherapy. In this study, the effects of curcumin on TP and ERCC1 expression induced by cisplatin in non-small-cell lung cancer (NSCLC) cell lines was investigated. Exposure of the NSCLC cells to various concentrations of curcumin (5-40 μM) down-regulates the mRNA and protein levels of TP and ERCC1 through destabilization of the mRNA and proteins via a mechanism involving inactivation of MKK1/2-extracellular signal-regulated kinase (ERK1/2). Depletion of endogenous TP or ERCC1 expression by transfection with specific small interfering RNAs significantly decreases cell viability in curcumin-exposed NSCLC cells. Curcumin enhances the sensitivity of cisplatin treatment for NSCLC through inactivation of ERK1/2 and by decreasing the TP and ERCC1 protein levels. Enhancement of ERK1/2 signaling by constitutively active MKK1/2 causes an increase in TP and ERCC1 protein levels and promotes cell viability after cotreatment with curcumin and cisplatin. Enhancement of the cytotoxicity to cisplatin by administration of curcumin is mediated by down-regulation of the expression levels of TP and ERCC1 and by inactivation of ERK1/2.
姜黄素（二芳基甲烷），一种从姜黄根茎中提取的酚类化合物，具有抗增殖和抗肿瘤特性。胸苷磷酸化酶（TP），嘧啶补救途径的一种酶，被认为是一个有吸引力的治疗靶点，其表达可以抑制 DNA 损伤剂诱导的癌细胞死亡。切除修复交叉互补基因 1（ERCC1）是一种参与核苷酸切除修复过程的蛋白质。ERCC1 基因在癌症中高表达，并与铂类化疗耐药性相关。在这项研究中，研究了姜黄素对顺铂诱导的非小细胞肺癌（NSCLC）细胞系中 TP 和 ERCC1 表达的影响。用不同浓度的姜黄素（5-40 μM）处理 NSCLC 细胞，通过使 MKK1/2-细胞外信号调节激酶（ERK1/2）失活的机制，使 mRNA 和蛋白质不稳定，下调 TP 和 ERCC1 的 mRNA 和蛋白水平。通过转染特异性小干扰 RNA 耗尽内源性 TP 或 ERCC1 表达，显著降低姜黄素暴露的 NSCLC 细胞中的细胞活力。姜黄素通过使 ERK1/2 失活并降低 TP 和 ERCC1 蛋白水平，增强 NSCLC 对顺铂治疗的敏感性。组成性激活 MKK1/2 增强 ERK1/2 信号会增加 TP 和 ERCC1 蛋白水平，并促进姜黄素和顺铂联合治疗后的细胞活力。通过下调 TP 和 ERCC1 的表达水平和使 ERK1/2 失活，姜黄素增强顺铂的细胞毒性。
