Role of hypoxia-inducible factor-alpha in hepatitis-B-virus X protein-mediated MDR1 activation.
The transition from chemotherapy-responsive cancer cells to chemotherapy-resistant cancer cells is mainly accompanied by the increased expression of multi-drug resistance 1 (MDR1). We found that hepatitis-B-virus X protein (HBx) increases the transcriptional activity and protein level of MDR1 in a hepatoma cell line, H4IIE. In addition, HBx overexpression made H4IIE cells more resistant to verapamil-uptake. HBx stabilized hypoxia-inducible factor-1alpha (HIF-1alpha) and induced the nuclear translocation of C/EBPbeta. Reporter gene analyses showed that HBx increased the reporter activity in the cells transfected with the reporter containing MDR1 gene promoter. Moreover, the luciferase reporter gene activity was significantly inhibited by HIF-1alpha siRNA but not by overexpression of C/EBP dominant negative mutant. These results imply that HBx increases the MDR1 transporter activity through the transcriptional activation of the MDR1 gene with HIF-1alpha activation, and suggest HIF-1alpha for the therapeutic target of HBV-mediated chemoresistance.
Han
Hyo-Kyung
HK
BK21 Project Team, College of Pharmacy, Chosun University, Gwangju 501-759, South Korea.
Han
Chang Yeob
CY
Cheon
Eun-Pa
EP
Lee
Jaewon
J
Kang
Keon Wook
KW
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D020112:Rhodamine 123 / Q000493:pharmacokinetics*; D015534:Trans-Activators; D014700:Verapamil / Q000493:pharmacokinetics*; D054334:Viral Regulatory and Accessory Proteins / Q000235:genetics / Q000378:metabolism*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011994:Recombinant Proteins; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D020112:Rhodamine 123; D014700:Verapamil