Cell Biology and Toxicology

, Volume 32, Issue 6, pp 483–497 | Cite as

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

  • Guiying Jin
  • Yang Li
  • Yuwen Zhu
  • Lisha Du
  • Junkai Yan
  • Qing Yang
Original Article


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.


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



ATP-binding cassette


Extracellular signal-regulated kinases


Ezrin, radixin, and moesin


Janus protein tyrosine kinase 2


Multidrug resistance


Multidrug resistance protein 2




Pregnane X receptor


Solute carrier




Sphingomyelin synthase


Thin layer chromatography



This work was supported by the National Natural Science Foundation of China (No. 81373396), the Key Biomedical Program of Shanghai (No. 12431900204), the Research Fund for the Doctoral Program of Higher Education of China (No. 20130071110037), and the Research Fund of the State Key Laboratory of Genetic Engineering, Fudan University.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.


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Copyright information

© Springer Science+Business Media Dordrecht 2016

Authors and Affiliations

  • Guiying Jin
    • 1
  • Yang Li
    • 1
  • Yuwen Zhu
    • 1
  • Lisha Du
    • 1
  • Junkai Yan
    • 2
  • Qing Yang
    • 1
    • 2
    • 3
  1. 1.State Key Laboratory of Genetic Engineering, Department of Biochemistry, School of Life SciencesFudan UniversityShanghaiChina
  2. 2.Shanghai Collaborative Innovation Center for Biomanufacturing (SCICB)East China University of Science and TechnologyShanghaiChina
  3. 3.Shanghai Engineering Research Center of Industrial MicroorganismsShanghaiChina

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