Epigentic mechanisms involved in the differential expression of MDR1 between gastric and colon cancer cells

Abstract

9708 Background: 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. Methods: To explore the mechanisms and roles of differential MDR1 mRNA expression in gastric and colon cancer cells, its chemosensitivity, function and epigenetic regulation of gene expression 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) were compared. Results: The RT-PCR assay revealed that MDR1 mRNAs in 7 colon cancer cell lines except SNU-C5 and HT-29 were variously expressed 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 increased 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 -668 and -719 except for SNU-484 in gastric cancer cells and SNU-C5, COLO320HSR, HT-29, HCT-116 in colon cancer cells were hypermethylated. MDR1 mRNA levels of SNU-5, -601, -668 and -719 in gastric cancer cells more increased when treated with 5-aza-2’-deoxycytidine (a methyltransferase inhibitor) and/or tricostatin A (histone deacetylase inhibitor), respectively. Conclusions: These results suggest that MDR1/Pgp plays more important roles in colon cancer cells than gastric cancer cells and their differential expression of MDR1 was regulated by epigenetic mechanisms. No significant financial relationships to disclose.