DIHYDROHEPTAPRENYL AND DIHYDRODECAPRENYL MONOPHOSPHATES INDUCE APOPTOSIS MEDIATED BY ACTIVATION OF CASPASE-3-LIKE PROTEASE

Dolichyl phosphate, an essential carrier lipid in the biosynthesis of N-linked glycoprotein, has been found to induce apoptosis in rat gliom a C6 cells and human monoblastic leukemia U937 cells. In the present s tudy, dolichyl phosphate and structurally related compounds were exami ned regarding their apoptosis-inducing activities in U937 cells, Dihyd roheptaprenyl and dihydrodecaprenyl phosphates, of which isoprene unit s are shorter than that of dolichyl phosphate, induced apoptosis in U9 37 cells. This phenomenon occurred in a dose-and time-dependent manner , as seen with dolichyl phosphate-induced apoptosis. Derivatives of th e same isoprene units of dolichyl phosphate, such as dolichol, dolicha l or dolichoic acid did not induce DNA fragmentation. Farnesyl phospha te and geranylgeranyl phosphate also failed to induce apoptosis. Durin g apoptosis, the caspase family of cysteine proteases play important r oles. We observed that apoptosis induced by dihydroprenyl phosphate wa s mediated by caspase-3-like (CPP32-like) activation but not by caspas e-1-like (ICE-Like) activation, This caspase-3-like activation was inh ibited by a specific inhibitor of caspase-3, DEVD-CHO, but not by an c aspase-1 inhibitor WAD-CHO. We interpret these results to mean that di hydroprenyl phosphates with more than seven isoprene units have apopto sis-inducing activity and that their signal is mediated by caspase-3-l ike activation. (C) 1998 Elsevier Science B.V.