Relation between P-glycoprotein expression and epigenetic mechanism in gastric and colon cancer cells

Abstract

The multidrug resistance (MDR) of tumor cells to anticancer drugs remains a major cause of treatment failure in cancer patients. The overexpression of P-glycopotein (Pgp), an MDR1 gene product, confers MDR to cancer cells. To explore the mechanisms and roles of differential MDR1 mRNA expression in gastric and colon cancer cells, the chemosensitivity, function and epigenetic regulation of gene expression were compared. in 10 gastric cancer cell lines (SNU-1, -5, -16, -216, -484, -601, -620, -638, -668 and -719) and 9 colon cancer cell lines (SNU-C1, -C4, -C5, COLO320HSR, LoVo, DLD-1, HT-29, HCT-8 and HCT-116). The RT-PCR assay revealed that MDR1 mRNAs were variously expressed in 7 colon cancer cell lines except SNU-C5 and HT-29 whereas those in gastric cancer cell lines were significantly lower and even not expressed in SNU-16 than those of colon cancer cell lines. The MTT assay showed comparative resistance of COLO320HSR (high level of MDR1 mRNA expression) to paclitaxel with that of SNU-C5 (low level of its expression). Flow cytometry showed that decreased rhodamine accumulation of COLO320HSR was enhanced by PSC833, a Pgp inhibitor, suggesting that Pgp works functionally as an efflux pump. The methylation specific PCR indicated that SNU-1, -5, -16, -216, -601, -620, -638, -688 and -719 except for SNU-484 in gastric cancer cells and SNU-C5, COLO320HSR, HT-29, HCT-116 in colon cancer cells were hypermethylated. Also, MDR1 mRNA levels in SNU-5, -601, -668 and -719 in gastric cancer cells increased when treated with 5-aza-2'-deoxycytidine (a methyltransferase inhibitor) and/or tricostatin A (histone deacetylase inhibitor), respectively. These results suggest that MDR1/Pgp plays more important roles in transporting function in colon cancer cells than gastric cancer cells and their differential expression of MDR1 is regulated by epigenetic mechanisms.