Troglitazone inhibits endothelial cell proliferation through suppression of casein kinase 2 activity.
Troglitazone, an agonist of peroxisome proliferator activated receptor gamma (PPARgamma), has been reported to inhibit endothelial cell proliferation by suppressing Akt activation. Recently, it has been also proposed that phosphatase and tensin homolog deleted from chromosome 10 (PTEN) plays an important role in such effect of troglitazone. However, the mechanism of how troglitazone regulates PTEN remains to be elucidated. We therefore investigated the effects of troglitazone on casein kinase 2 (CK2), which is known to negatively regulate PTEN activity. Troglitazone significantly inhibited serum-induced proliferation of HUVEC in a concentration dependent manner. Serum-induced Akt and its downstream signaling pathway activation was attenuated by troglitazone (10 microM) pretreatment. The phosphorylation of PTEN, which was directly related to Akt activation, was decreased with troglitazone pretreatment and was inversely proportional to CK2 activity. DRB, a CK2 inhibitor, also showed effects similar to that of troglitazone on Akt and its downstream signaling molecules. In conclusion, our results suggest that troglitazone inhibits proliferation of HUVECs through suppression of CK2 activity rendering PTEN to remain activated, and this effect of troglitazone in HUVECs seems to be PPARgamma independent.
Lee
Kuy-Sook
KS
Center for Biological Sciences, Division of Cardiovascular Diseases, National Institute of Health, Seoul, Republic of Korea.
Park
Jin-Hee
JH
Lee
Seahyoung
S
Lim
Hyun-Joung
HJ
Jang
Yangsoo
Y
Park
Hyun-Young
HY
D047390:Casein Kinase II / Q000037:antagonists & inhibitors*; D002464:Cell Migration Inhibition; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology*; D004004:Dichlororibofuranosylbenzimidazole / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects*; D006801:Humans; D047495:PPAR gamma / Q000819:agonists; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology*; D000077288:Troglitazone
D002839:Chromans; D047495:PPAR gamma; D045162:Thiazolidinediones; D004004:Dichlororibofuranosylbenzimidazole; D047390:Casein Kinase II; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D051059:PTEN Phosphohydrolase; D000077288:Troglitazone