title: Casein Kinase 2 (CK2)-mediated Phosphorylation of Hsp90β as a Novel Mechanism of Rifampin-induced MDR1 Expression.
abstract: The P-glycoprotein (P-gp) encoded by the MDR1 gene is a drug-exporting transporter located in the cellular membrane. P-gp induction is regarded as one of the main mechanisms underlying drug-induced resistance. Although there is great interest in the regulation of P-gp expression, little is known about its underlying regulatory mechanisms. In this study, we demonstrate that casein kinase 2 (CK2)-mediated phosphorylation of heat shock protein 90β (Hsp90β) and subsequent stabilization of PXR is a key mechanism in the regulation of MDR1 expression. Furthermore, we show that CK2 is directly activated by rifampin. Upon exposure to rifampin, CK2 catalyzes the phosphorylation of Hsp90β at the Ser-225/254 residues. Phosphorylated Hsp90β then interacts with PXR, causing a subsequent increase in its stability, leading to the induction of P-gp expression. In addition, inhibition of CK2 and Hsp90β enhances the down-regulation of PXR and P-gp expression. The results of this study may facilitate the development of new strategies to prevent multidrug resistance and provide a plausible mechanism for acquired drug resistance by CK2-mediated regulation of P-gp expression.
authors.affiliation: From the Department of Pharmacology and the Institute for Clinical and Translational Research, Catholic Kwandong University College of Medicine, Gangneung 210-701, Korea, the Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan 614-735, Korea, the Department of Clinical Pharmacology, Inje University Busan Paik Hospital, Busan 614-735, Korea.
authors.forename: So Won
authors.initials: SW
authors.lastname: Kim
authors.affiliation: the Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan 614-735, Korea.
authors.forename: Md
authors.initials: M
authors.lastname: Hasanuzzaman
authors.affiliation: the Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan 614-735, Korea.
authors.forename: Munju
authors.initials: M
authors.lastname: Cho
authors.affiliation: the Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan 614-735, Korea.
authors.forename: Ye Rang
authors.initials: YR
authors.lastname: Heo
authors.affiliation: the Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan 614-735, Korea.
authors.forename: Min-Jung
authors.initials: MJ
authors.lastname: Ryu
authors.affiliation: the Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan 614-735, Korea.
authors.forename: Na-Young
authors.initials: NY
authors.lastname: Ha
authors.affiliation: the Bio-MAX Institute, Seoul National University, Seoul 151-742, Korea, and.
authors.forename: Hyun June
authors.initials: HJ
authors.lastname: Park
authors.affiliation: the Agriculture and Biotechnology Department, Noroo Holdings Co. Ltd., Seoul 135-983, Korea.
authors.forename: Hyung-Yeon
authors.initials: HY
authors.lastname: Park
authors.affiliation: the Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan 614-735, Korea, the Department of Clinical Pharmacology, Inje University Busan Paik Hospital, Busan 614-735, Korea, phshinjg@gmail.com.
authors.forename: Jae-Gook
authors.initials: JG
authors.lastname: Shin
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D020816:Amino Acid Motifs; D047390:Casein Kinase II / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D062105:Molecular Docking Simulation; D010766:Phosphorylation / Q000187:drug effects; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism; D012293:Rifampin / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D018841:HSP90 Heat-Shock Proteins; C493165:HSP90AB1 protein, human; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; C570325:CSNK2A1 protein, human; D047390:Casein Kinase II; D012293:Rifampin
keywords: ABC transporter; casein kinase 2 (CK2); colorectal cancer; drug resistance; heat shock protein 90 (Hsp90); heat shock protein 90 β (Hsp90β); permeability glycoprotein (P-gp); pregnane X receptor (PXR); rifampin; tuberculosis