Effect of Candesartan cilexetil as a sensitive and effective inhibitor of SHP-1 on insulin signaling pathway

Abstract

The protein tyrosine phosphatases(PTPs) comprise a family of enzymes that specifically dephosphorylate tyrosyl residues. Among them, SHP-1 has been regarded as one of the best validated intracellular tyrosine phosphatases. Downregulation of SHP-1 has shown remarkable efficacy in improving insulin sensitivity in vivo in insulin signaling pathway. In this study, we found the role of Candesartan cilexetil targeting at SHP-1. The results indicate that Candesartan cilexetil was a competitive inhibitor to SHP-1(IC₅₀=85.6 μmol/L and K _i=24 μmol/L). We also found that Candesartan cilexetil was more sensitive towards SHP-1 compared with other PTPs. Through the consequence of Western blotting, it showed that Candesartan cilexetil can strengthen the level of tyrosine phosphorylation of several key cellular proteins[such as insulin receptor(IR), insulin receptor substrate(IRS) and ERK]_in insulin signaling pathway in HepG₂ cells and improve the insulin sensitivity through inhibiting the protein phosphorylation of SHP-1. These findings showed that Candesartan cilexetil might be an important inhibitor of SHP-1 and had a great application potential in the treatment of diabetes through inhibiting the level of SHP-1 in insulin signaling pathway.

Keywords

SHP-1 / Candesartan cilexetil / Inhibitor / Insulin sensitivity

References

[1] Li W L, Zheng H C, Bukuru J. Journal of Ethnopharmacology, 2004, 92: 1.

[2] Neel B G, Tonks N K. Curr. Opin. Cell Biol., 1997, 9: 193.

[3] Hunter T. Cell, 2000, 100: 113.

[4] Zhang Z Y. Curr. Opin. Chem. Biol., 2001, 5: 416.

[5] Li W N, Zhuang Y, Li H, Sun Y, Fu Y, Wu X X, Zhao Z Z, Fu X Q. Chem. Res. Chinese Universities, 2008, 24(5): 592.

[6] Tonks N K, Neel B G. Curr. Opin. Cell Biol., 2001, 13: 182.

[7] Maegawa H. J. Biol. Chem., 1999, 274: 30236.

[8] Dubois M J. Nat. Med., 2006, 12: 549.

[9] Dubois M J, Bergeron S, Kim H J, Dombrowski L, Perreault M, Fournès B, Faure R, Olivier M, Beauchemin N, Shulman G I, Siminovitch K A, Kim J K, Marette A. Nat. Med., 2006, 12: 549.

[10] Goldstein B J. J. Clin. Endocrinol. Metab., 2002, 87: 2474.

[11] Xie X N, Zhang C L, Xun E N, Wang J X, Zhang H, Wang L, Wang Z. Chem. Res. Chinese Universities, 2012, 28(2): 225.

[12] Li W N, Zhuang Y, Fu X Q, Zhao Z Z J. Chem. Res. Chinese Universities, 2008, 24(5): 592.

[13] Saltiel A R, Pessin J E. Trends Cell Biol., 2002, 12: 65.

[14] Ostman A, Bohmer F D. Trends Cell Bio., 2001, 11: 258.

[15] Bousquet C, Delesque N, Lopez F, Saint-Laurent N, Estève J P, Bedecs K, Buscail L, Vaysse N, Susini C. J. Biol. Chem., 1998, 273: 7099.

[16] Penha A M, Burkhardt E, Schaeffel F, Marita P. Mol. Vis., 2012, 18: 2608.

[17] Denner L A, Rodriguez-Rivera J, Haidacher S J, Jahrling J B, Carmical J R, Hernandez C M, Zhao Y, Sadygov R G, Starkey J M, Spratt H, Luxon B A, Wood T G, Dineley K T. J. Neurosci., 2012, 32: 16725.