title: P-glycoprotein enhances radiation-induced apoptotic cell death through the regulation of miR-16 and Bcl-2 expressions in hepatocellular carcinoma cells.
abstract: P-glycoprotein (Pgp), an efflux pump, was confirmed the first time to regulate the expressions of miR/gene in cells. Pgp is known to be associated with multidrug resistance. RHepG2 cells, the multidrug resistant subline of human hepatocellular carcinoma HepG2 cells, expressed higher levels of Pgp as well as miR-16, and lower level of Bcl-2 than the parental cells. In addition, RHepG2 cells were more radiation sensitive and showed more pronounced radiation-induced apoptotic cell death than the parental cells. Mechanistic analysis revealed that transfection with mdr1 specific antisense oligos suppressed radiation-induced apoptosis in HepG2 cells. On the other hand, ectopic mdr1 expression enhanced radiation-induced apoptosis in HepG2 cells, SK-HEP-1 cells, MiHa cells, and furthermore, induced miR-16 and suppressed its target gene Bcl-2 in HepG2 cells. Moreover, the enhancement effects of Pgp and miR-16 on radiation-induced apoptosis were counteracted by overexpression of Bcl-2. The Pgp effect on miR-16/Bcl-2 was suppressed by Pgp blocker verapamil indicating the importance of the efflux of Pgp substrates. The present study is the first to reveal the role of Pgp in regulation of miRNA/gene expressions. The findings may provide new perspective in understanding the biological function of Pgp.
authors.affiliation: School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China. tsunyee291@yahoo.com.hk
authors.forename: Tsun Yee
authors.initials: TY
authors.lastname: Tsang
authors.forename: Wan Yee
authors.initials: WY
authors.lastname: Tang
authors.forename: Judy Yuet Wa
authors.initials: JY
authors.lastname: Chan
authors.forename: Ngai Na
authors.initials: NN
authors.lastname: Co
authors.forename: Chi Lam
authors.initials: CL
authors.lastname: Au Yeung
authors.forename: Pak Lun
authors.initials: PL
authors.lastname: Yau
authors.forename: Siu Kai
authors.initials: SK
authors.lastname: Kong
authors.forename: Kwok Pui
authors.initials: KP
authors.lastname: Fung
authors.forename: Tim Tak
authors.initials: TT
authors.lastname: Kwok
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D017209:Apoptosis / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005720:Gamma Rays; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D011836:Radiation Tolerance / Q000235:genetics*; D014700:Verapamil / Q000494:pharmacology
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; C505362:MIRN16 microRNA, human; D035683:MicroRNAs; D019253:Proto-Oncogene Proteins c-bcl-2; D014700:Verapamil