Abstract 1699: Thymidylate synthase and thymidine phosphorylase expression contributes to cisplatin resistance

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) were 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) decreases 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 increases cisplatin-induced cell death and growth inhibition. Moreover, pemetrexed (TS inhibitor) enhances cisplatin-induced cytotoxic effects. Combined treatment with 5-FU can decrease cisplatin-induced ERK1/2 activation and the induction of TS and TP, which can subsequently result in synergistic cytotoxic effects. Enforced expression of constitutive active MKK1/2 vectors rescue 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 enhances the drug sensitivity to cisplatin and/or 5-FU in lung cancer cells. We conclude that the up-regulation of ERK1/2-dependent TS and TP can protect human lung cancer cells from cisplatin-induced cytotoxicity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1699. doi:10.1158/1538-7445.AM2011-1699