Abstract 3607: The effect of gefitinib on the expression of c-MYC and TSP-1 in cancer cells

Abstract

Abstract Gefitinib is a selective inhibitor of epidermal growth factor receptor tyrosine kinase, and is known to suppress tumor angiogenesis. We previously reported that gefitinib suppressed E2F-1 expression and telomerase activity in A431 and A549 cells. The expression of hTERT was increased by c-MYC, whereas we found that 5-FU decreased the expression of c-MYC and increased Thrombospondin-1 (TSP-1) expression. In the present study, we examined the effects of gefitinib on the expression of c-MYC and TSP-1 in human epidermmoid carcinoma A431 and lung adenocarcinoma A549 cells. Gefitinib suppressed the expression of c-MYC in both of two cell lines within 12 hours after gefitinib exposure, however, the expression of c-MYC mRNA was reduced only in A431 cells. A549 cells are known to have K-RAS mutation but A431 cells do not. We suppose that post-transcriptional inhibition or degradation of c-MYC had been induced by the treatment with gefitinib. MG132, a proteasome inhibitor, could inhibit the suppression of c-MYC expression by gefitinib exposure in both of these cells. Thus, the promotion of c-MYC degradation may be one of the mechanisms of the suppression of c-MYC expression by gefitinib exposure on these cells. On the other hand, in A549 cells, 5-20μM of gefitinib suppressed the expression of c-MYC after incubation for 96 hours too, while TSP-1 expression was increased by gefitinib. In A431 cells, 0.12-1.0μM of gefitinib affected the expression of c-MYC and TSP-1. As in A549 cells, TSP-1 expression was up-regulated but the expression of c-MYC was attenuated by gefitinib. Our findings suggest that the anti-angiogenic effects of gefitinib might be, at least in part, due to TSP-1 expression augmented by gefitinib. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3607.