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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Differential Roles for Cytosolic and Microsomal Ca²⁺-Independent Phospholipase A₂ in Cell Growth and Maintenance of Phospholipids

Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, Georgia

Physiological roles of microsomal (iPLA₂) and cytosolic (iPLA₂)Ca²⁺-independent phospholipase A₂ were determined in two different epithelial cell models. R- and S-enantiomers of the iPLA₂ inhibitor bromoenol lactone (BEL) were isolated and shown to selectively inhibit iPLA₂ and iPLA₂, respectively. The effect of these enantiomers on cell growth was assessed in human embryonic kidney 293 and Caki-1 cells using 3-(4-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT). S-BEL (0-5.0 µM) decreased MTT staining 35% after 24 h compared with control cells, whereas treatment with either R-BEL or R/S-BEL induced 15% decreases. Neither R-BEL nor S-BEL induced cell death as determined by annexin V and propidium iodide staining. Transfection of cells with iPLA₂ siRNA reduced MTT staining approximately 35%, whereas transfection of cells with iPLA₂ siRNA only decreased MTT staining 10 to 15% compared with control cells. The effect of iPLA₂ and iPLA₂ siRNA on cell number and protein was also determined, and iPLA₂ siRNA decreased cell number and protein 25% compared with control cells. In contrast, iPLA₂ siRNA decreased cell number, but not cellular protein, compared with control cells. Selective inhibition of iPLA₂, but not iPLA₂, decreased several arachidonic acid-containing phospholipids, including 16:1-20:4, 16:0-20:4, 18:1-20:4, and 18:0-20:4 phosphatidylcholine, showing that the ability of iPLA₂ inhibitors to decrease cell growth correlates with their ability to decrease arachidonic acid-containing phospholipids. These data show that iPLA₂ inhibition results in greater decreases in cell growth and proliferation than iPLA₂, identifies specific phospholipids whose expressions are differentially regulated by iPLA₂ and iPLA₂, and suggests novel roles for iPLA₂ in cell growth.

Address correspondence to: Dr. Brian S. Cummings, Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, GA 30602. E-mail: bsc{at}rx.uga.edu

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