Effect of Candesartan Cilexetil as a Sensitive and Effective Inhibitor of SHP-1 on Insulin Signaling Pathway

• Published in: Chemical research in Chinese universities Vol. 29; no. 4; pp. 730 - 734
• Main Authors: Zhang, Lei, Zhang, Shi-tao, Zhang, Xiao-ping, Sun, Jing, Wang, Yong-sen, Liu, Yue-long, Xue, Miao-miao, Wang, Zhi, Xing, Shu, Ma, Jun-feng, Li, Wan-nan, Fu, Xue-qi
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.08.2013; Key Laboratory for Molecular Enzymology and Engineering, Ministry of Education,Jilin University, Changchun 130012, P.R.China; State Engineering Laboratory of AIDS Vaccine, Jilin University,Changchun 130012, R.P.China%Clinical Laboratory, China-Japan Union Hospital, Jilin University, Changchun 130033, P.R.China
• Subjects: Analytical Chemistry; Chemistry; Chemistry and Materials Science; Chemistry/Food Science; HepG2细胞; Inorganic Chemistry; Organic Chemistry; Physical Chemistry; Western印迹法; 信号转导通路; 信号通路; 抑制剂; 胰岛素受体底物; 胰岛素敏感性; 蛋白酪氨酸磷酸酶; Candesartan cilexetil; Inhibitor; SHP-1; Insulin sensitivity
• ISSN: 1005-9040; 2210-3171
• DOI: 10.1007/s40242-013-2505-0

The protein tyrosine phosphatases（PTPs） comprise a family of enzymes that specifically dephosphorylate tyrosyl residues. Among them, SHP-I has been regarded as one of the best validated intracellular tyrosine phospha- tases. 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 ~tmol/L and Ki=24 ~tmol/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 applica- tion potential in the treatment of diabetes through inhibiting the level of SHP-1 in insulin signaling pathway.