tailieunhanh - Báo cáo khoa học: Enhanced apoptosis through farnesol inhibition of phospholipase D signal transduction

Farnesol is a catabolite of the cholesterol biosynthetic pathway that prefer-entially causes apoptosis in tumorigenic cells. Phosphatidylcholine (PC), phosphatidic acid (PA), and diacylglycerol (DAG) were able to prevent induction of apoptosis by farnesol. Primary alcohol inhibition of PC cata-bolism by phospholipase D augmented farnesol-induced apoptosis. Exogen-ous PC was unable to prevent the increase in farnesol-induced apoptosis by primary alcohols, whereas DAG was protective. | iFEBS Journal Enhanced apoptosis through farnesol inhibition of phospholipase D signal transduction Marcia M. Taylor1 Kendra MacDonald1 Andrew J. Morris2 and Christopher R. McMaster1 1 Atlantic Research Centre Dalhousie University Halifax Canada 2 Department of Celland DevelopmentalBiology Lineberger Comprehensive Cancer Center The University of North Carolina at Chapel Hill USA Keywords apoptosis diacylglycerol farnesol phosphatidic acid phosphatase phospholipase D Correspondence C. McMaster Atlantic Research Centre Departments of Pediatrics and Biochemistry Molecular Biology Dalhousie University 5849 University Avenue Room C302 Halifax Nova Scotia B3H 4H7 Canada Fax 1 902 494 1394 Tel 1 902 494 2953 E-mail Received 15 May 2005 revised 3 August 2005 accepted 11 August 2005 Farnesol is a catabolite of the cholesterol biosynthetic pathway that preferentially causes apoptosis in tumorigenic cells. Phosphatidylcholine PC phosphatidic acid PA and diacylglycerol DAG were able to prevent induction of apoptosis by farnesol. Primary alcohol inhibition of PC catabolism by phospholipase D augmented farnesol-induced apoptosis. Exogenous PC was unable to prevent the increase in farnesol-induced apoptosis by primary alcohols whereas DAG was protective. Farnesol-mediated apoptosis was prevented by transformation with a plasmid coding for the PA phosphatase LPP3 but not by an inactive LPP3 point mutant. Farnesol did not directly inhibit LPP3 PA phosphatase enzyme activity in an in vitro mixed micelle assay. We propose that farnesol inhibits the action of a DAG pool generated by phospholipase D signal transduction that normally activates an antiapoptotic pro-proliferative target. doi Phosphatidylcholine PC is the major membrane lipid found in eukaryotic cells comprising w 50 of phospholipid mass. PC plays a major role in maintaining the physical properties of membranes and is also a reservoir of signaling molecules 1-4 .

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