Casein Kinase 2 (CK2)-mediated Phosphorylation of Hsp90β as a Novel Mechanism of Rifampin-induced MDR1 Expression

• Published in: The Journal of biological chemistry Vol. 290; no. 27; pp. 17029 - 17040
• Main Authors: Kim, So Won, Hasanuzzaman, Md, Cho, Munju, Heo, Ye Rang, Ryu, Min-Jung, Ha, Na-Young, Park, Hyun June, Park, Hyung-Yeon, Shin, Jae-Gook
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03-07-2015; American Society for Biochemistry and Molecular Biology
• Subjects: ABC transporter; Amino Acid Motifs; ATP Binding Cassette Transporter, Subfamily B - genetics; ATP Binding Cassette Transporter, Subfamily B - metabolism; casein kinase 2 (CK2); Casein Kinase II - chemistry; Casein Kinase II - genetics; Casein Kinase II - metabolism; Cell Line, Tumor; colorectal cancer; drug resistance; Gene Expression Regulation - drug effects; heat shock protein 90 (Hsp90); heat shock protein 90 β (Hsp90β); HSP90 Heat-Shock Proteins - chemistry; HSP90 Heat-Shock Proteins - genetics; HSP90 Heat-Shock Proteins - metabolism; Humans; Molecular Docking Simulation; permeability glycoprotein (P-gp); Phosphorylation - drug effects; Pregnane X Receptor; pregnane X receptor (PXR); Receptors, Steroid - genetics; Receptors, Steroid - metabolism; rifampin; Rifampin - chemistry; Rifampin - pharmacology; Signal Transduction; tuberculosis; colorectal cancer; heat shock protein 90 (Hsp90); rifampin; tuberculosis; casein kinase 2 (CK2); drug resistance; permeability glycoprotein (P-gp); heat shock protein 90 β (Hsp90β); ABC transporter; pregnane X receptor (PXR)
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M114.624106

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.
Background: Rifampin is a representative inducer of P-gp, and the only known mechanism is binding between rifampin and PXR.
Results: Rifampin directly activates CK2, which phosphorylates Hsp90β. Consequently, PXR increases, and P-gp expression is induced.
Conclusion: A mechanism for inducing P-gp expression by rifampin exposure is newly identified.
Significance: A strategy for overcoming P-gp-derived drug resistance is suggested.