Emodin enhances cisplatin-induced cytotoxicity via down-regulation of ERCC1 and inactivation of ERK1/2.
Emodin, a tyrosine kinase inhibitor, is a natural anthraquinone derivative found in the roots and rhizomes of numerous plants; it exhibits an anticancer effect on many malignancies. The most important chemotherapeutic agent for patients with advanced non-small cell lung cancer (NSCLC) is a platinum-containing compound such as cisplatin or carboplatin. The molecular mechanism underlying decreased NSCLC cell viability after treatment with emodin and cisplatin is unclear. Therefore, the aim of this study was to assess the cytotoxic effect of combined emodin and cisplatin on NSCLC cell lines and to clarify underlying molecular mechanisms. Exposure of human NSCLC cells to emodin decreased cisplatin-elicited ERK1/2 activation and ERCC1 protein induction by increasing instability of ERCC1 protein. Cisplatin alone did not affect expression of ERCC1 mRNA. However, emodin alone or combined with cisplatin significantly decreased expression of ERCC1 mRNA levels. Enhancement of ERK1/2 activation by transfection with constitutively active MKK1/2 (MKK1/2-CA) vector increased ERCC1 protein levels and protein stability, as well as increasing viability of NSCLC cells treated with emodin and cisplatin. In contrast, blocking ERK1/2 activation by U0126 (an MKK1/2 inhibitor) decreased cisplatin-elicited ERCC1 expression and enhanced cisplatin-induced cytotoxicity. Depletion of endogenous ERCC1 expression by si-ERCC1 RNA transfection significantly enhanced cisplatin's cytotoxic effect. In conclusion, ERCC1 protein protects NSCLC cells from synergistic cytotoxicity induced by emodin and platinum agents. Further investigation of combined emodin and cisplatin may lead to novel therapy in the future for NSCLC through down-regulating expression of ERCC1.
Ko
Jen-Chung
JC
Department of Internal Medicine, Hsinchu Hospital, Department of Health, The Executive Yuan, Taiwan.
Su
Ying-Jhen
YJ
Lin
Szu-Ting
ST
Jhan
Jhih-Yuan
JY
Ciou
Shih-Ci
SC
Cheng
Chao-Min
CM
Chiu
Yu-Fan
YF
Kuo
Ya-Hsun
YH
Tsai
Min-Shao
MS
Lin
Yun-Wei
YW
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002070:Butadienes / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004357:Drug Synergism; D004642:Emodin / Q000008:administration & dosage / Q000009:adverse effects; D004720:Endonucleases / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D048369:MAP Kinase Kinase 1 / Q000096:biosynthesis / Q000235:genetics; D048052:Mitogen-Activated Protein Kinase 3 / Q000096:biosynthesis* / Q000235:genetics; D009570:Nitriles / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics
D002070:Butadienes; D004268:DNA-Binding Proteins; D009570:Nitriles; D034741:RNA, Small Interfering; C113580:U 0126; D048052:Mitogen-Activated Protein Kinase 3; D048369:MAP Kinase Kinase 1; C071447:ERCC1 protein, human; D004720:Endonucleases; D004642:Emodin; D002945:Cisplatin