Casein Kinase 2 (CK2)-mediated Phosphorylation of Hsp90? 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 90? (Hsp90?) 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 Hsp90? at the Ser-225/254 residues. Phosphorylated Hsp90? 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 Hsp90? 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.

SUBMITTER: Kim SW 

PROVIDER: S-EPMC4505446 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature