Suppression of BCRP Expression and Restoration of Sensitivity to Chemotherapy in Multidrug-Resistant Hepatocellular Carcinoma Cell Line HEPG2/ADM by RNA Interference

Abstract

Breast cancer resistance protein (BCRP) is an ATP-binding cassette multidrug transporter that confers resistance to various anticancer drugs like Adriamycin. Overexpression of BCRP confers multidrug resistance (MDR) in hepatocellular carcinoma cells and is a frequent impediment to successful chemotherapy. We evaluated a new approach using RNA interference for the specific knockdown of BCRP in hepatocellular carcinoma cells. To overcome the BCRP-mediated atypical multidrug drug resistance, one small interfering RNA construct (RNAi) targeting one special region of BCRP gene were designed to inhibit the atypical MDR expression by transfecting them into HepG2/ADM cell lines. We found that the overexpression of BCRP gene was suppressed efficiently by the introduction of small interfering RNA, which caused sequence specific gene silence. The level of BCRP mRNA reduced to 22.55% after transfected by pSUPER-BCRPs compared with those of the controls. Similarly, the level of BCRP decreased too. Furthermore, the sensitivity to Adriamycin of pSUPER-BCRPs-treated HEPG2/ADM cells is increased 3.55-fold compared to their control (p<0.05). The relative reverse rate of HepG2/ADM cell to Adriamycin is 72.2%. These data indicated that pSUPER-BCRPs could modulate MDR and may present a new approach to overcome BCRP-mediated drug resistance in HEPG2/ADM cells. It may reverse multidrug resistance phenotype and therefore provide promising therapeutic modalities in the treatment of hepatocellular carcinoma.