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Up-regulation of ERK1/2-dependent thymidylate synthase and thymidine phosphorylase contributes to cisplatin resistance in human non-small cell lung cancer cells.
MedLine Citation:
PMID:  21444628     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Chemotherapy for advanced human non-small cell lung cancer (NSCLC) includes platinum-containing compound such as cisplatin in combination with a second- or third-generation cytotoxic agents. 5-Fluorouracil (5-FU) belongs to anti-metabolite chemotherapeutics, and its mechanism of cytotoxicity is involved in inhibition of thymidylate synthase (TS). TS and thymidine phosphorylase (TP) are key enzymes of the pyrimidine salvage pathway. In this study, we have examined the molecular mechanism of TS and TP in regulating the drug sensitivity to cisplatin in NSCLC cell lines. Cisplatin could increase the phosphorylation of MKK1/2-ERK1/2 and the protein levels of TS and TP through enhancing the protein stability in A549 and H1975 cells. Blocking ERK1/2 activation by MKK1/2 inhibitor (U0126) decreased TS and TP protein levels in both cell lines treated with cisplatin. Depletion of endogenous TS or TP expression by specific small interfering RNA transfection significantly increased cisplatin-induced cell death and growth inhibition. Combined treatment with 5-FU could decrease cisplatin-induced ERK1/2 activation and the induction of TS and TP, which subsequently resulted in synergistic cytotoxic effects. Enforced expression of constitutive active MKK1/2 vectors rescued the protein levels of phospho-ERK1/2, TS and TP, and the cell viability which were decreased by cisplatin and 5-FU combination. In contrast, U0126 enhanced the drug sensitivity to cisplatin and/or 5-FU in lung cancer cells. In conclusion, the up-regulation of ERK1/2-dependent TS and TP can protect human lung cancer cells from cisplatin-induced cytotoxicity.
Authors:
Yun-Wei Lin; Jen-Chung Ko; Min-Shao Tsai; Yu-Fan Chiu; Shao-Hsing Weng; Ya-Hsun Kuo
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-3-28
Journal Detail:
Title:  The Journal of pharmacology and experimental therapeutics     Volume:  -     ISSN:  1521-0103     ISO Abbreviation:  -     Publication Date:  2011 Mar 
Date Detail:
Created Date:  2011-3-29     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
1 National Chiayi University;
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