Abstract
Abstract P-glycoprotein (Pgp) overexpression is frequently associated with multidrug resistance in cancer cells. Pgp is an efflux pump and is encoded by human mdr1 gene. The expression of mdr1 may be regulated by promoter methylation catalyzed by DNA methyltransferases (DNMTs). S-adenosyl-L-methionine (SAMe) is an important cofactor of DNMTs. Although SAMe has been shown to regulate promoter methylation of various genes, the effect of SAMe on Pgp expression and chemosensitivity of cancer cells are however not known. The aim of the present study is to examine the role of SAMe in the regulation of Pgp expression and drug sensitivity of human cancer cells. By qRT-PCR and Western blot analyses, incubation with 1mg/ml SAMe for 24h was found to increase mdr1 mRNA and Pgp protein levels in human hepatocellular carcinoma HepG2 cells, human colorectal adenocarcinoma CaCO-2 cells and human leukemia Jurkat-T cells. Methylation specific PCR and bisulfite DNA sequencing analyses revealed that the SAMe treatment induces hypomethylation of mdr1 promoter. Moreover, SAMe decreased intracellular doxorubicin accumulation and increased doxorubicin resistance in human cancer cells as assessed by doxorubicin accumulation assay and MTT assay. Furthermore, in human colorectal carcinoma HCT-116 parent cells and DNMTs knock-out sublines, SAMe induced Pgp expression in HCT-116 parent and DNMT3b knock-out subline but not in DNMT1 and DNMT1/DNMT3b double knockout sublines. The results from the present study therefore suggest that SAMe induces hypomethylation of mdr1 promoter, Pgp expression, and thus drug resistance in human cancer cells. Furthermore, DNMT1 appeared to be important in the effect of SAMe on mdr1. 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 1702. doi:10.1158/1538-7445.AM2011-1702
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