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Cell Biol Toxicol. 2016 Dec;32(6):483-497. Epub 2016 Jul 9.

SMS regulates the expression and function of P-gp and MRP2 in Caco-2 cells.

Jin G1, Li Y1, Zhu Y1, Du L1, Yan J2, Yang Q3,4,5.

Author information

1
State Key Laboratory of Genetic Engineering, Department of Biochemistry, School of Life Sciences, Fudan University, Songhu Road 2005, Shanghai, 200438, China.
2
Shanghai Collaborative Innovation Center for Biomanufacturing (SCICB), East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237, China.
3
State Key Laboratory of Genetic Engineering, Department of Biochemistry, School of Life Sciences, Fudan University, Songhu Road 2005, Shanghai, 200438, China. yangqing68@fudan.edu.cn.
4
Shanghai Collaborative Innovation Center for Biomanufacturing (SCICB), East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237, China. yangqing68@fudan.edu.cn.
5
Shanghai Engineering Research Center of Industrial Microorganisms, Songhu Road 2005, Shanghai, 200438, China. yangqing68@fudan.edu.cn.

Abstract

Sphingomyelin synthase (SMS) has two isoforms of SMS1 and SMS2, the last enzyme involved in the biosynthesis of sphingomyelin (SM), and has impact on the expression of membrane proteins. In the present study, we explored the potential effects of SMS on drug transporters, a special family of membrane proteins in human intestinal epithelial Caco-2 cells. The specific knockdown of SMS1 or SMS2 with siRNA in Caco-2 cells substantially decreased the expression and function of P-glycoprotein (P-gp) and multidrug resistance protein 2 (MRP2) rather than other drug transporters MRP1, MRP3, PEPT1, OATP2B1, and BCRP. In the SMS1 stable overexpressed Caco-2 cell line, the expression levels of P-gp and MRP2 and transcription factor pregnane X receptor (PXR) were upregulated and the phosphorylation levels of signaling pathways janus protein tyrosine kinase 2 (JAK-2) and extracellular signal-regulated kinases (ERK) were also evidently increased; however, the upregulated mRNA expression levels of PXR, P-gp, and MRP2 were diminished by inhibiting the phosphorylation of ERK and JAK-2. Furthermore, the SMS1 overexpression in Caco-2 cells altered the expression levels of ERM proteins ezrin and moesin, which are closely connected to the function of drug transporters. In conclusion, we herein demonstrate for the first time that in Caco-2 cells SMS regulates the expression and function of drug transporters P-gp and MRP2, and their regulator PXR is mediated by phosphorylated ERK and JAK-2 signaling pathways.

KEYWORDS:

Multidrug resistance protein 2; P-glycoprotein; Phosphorylated signal pathways; Pregnane X receptor; Sphingomyelin synthase

PMID:
27394416
DOI:
10.1007/s10565-016-9348-7
[Indexed for MEDLINE]

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