Signaling through cholesterol esterification: a new pathway for the cholecystokinin 2 receptor involved in cell growth and invasion

Several studies indicate that cholesterol esterification is deregulated in cancers. The present study aimed to characterize the role of cholesterol esterification in proliferation and invasion of two tumor cells expressing an activated cholecystokinin 2 receptor (CCK2R). A significant increase in cholesterol esterification and activity of Acyl-CoA:cholesterol acyltransferase (ACAT) was measured in tumor cells expressing a constitutively activated oncogenic mutant of the CCK2R (CCK2R-E151A cells) compared with nontumor cells expressing the wild-type CCK2R (CCK2R-WT cells). Inhibition of cholesteryl ester formation and ACAT activity by Sah58-035, an inhibitor of ACAT, decreased by 34% and 73% CCK2R-E151A cell growth and invasion. Sustained activation of CCK2R-WT cells by gastrin increased cholesteryl ester production while addition of cholesteryl oleate to the culture medium of CCK2R-WT cells increased cell proliferation and invasion to a level close to that of CCK2R-E151A cells. In U87 glioma cells, a model of autocrine growth stimulation of the CCK2R, inhibition of cholesterol esterification and ACAT activity by Sah58-035 and two selective antagonists of the CCK2R significantly reduced cell proliferation and invasion. In both models, cholesteryl ester formation was found dependent on protein kinase zeta/extracellular signal-related kinase 1/2 (PKC zeta/ERK1/2) activation. These results show that signaling through ACAT/cholesterol esterification is a novel pathway for the CCK2R that contributes to tumor cell proliferation and invasion.-Paillasse, M. R., P. de Medina., G. Amouroux, L. Mhamdi, M. Poirot, and S. Silvente-Poirot. Signaling through cholesterol esterification: a new pathway for the cholecystokinin 2 receptor involved in cell growth and invasion. J.Lipid Res. 2009. 50: 2203-2211.