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CELLULAR AND MOLECULAR

Cilostazol Prevents Tumor Necrosis Factor--Induced Cell Death by Suppression of Phosphatase and Tensin Homolog Deleted from Chromosome 10 Phosphorylation and Activation of Akt/Cyclic AMP Response Element-Binding Protein Phosphorylation

Department of Pharmacology (K.W.H., K.Y.K., H.K.S., J.H.L., J.M.C., C.D.K., W.S.L., B.Y.R.), College of Medicine and Research Institute of Genetic Engineering (K.W.H.), Pusan National University, Busan, Korea; and Institute of Cardiovascular Research (Y.-G.K.), Chonbuk National University, Chonbuk, Korea

This study examines the signaling mechanism by which cilostazol prevents neuronal cell death. Cilostazol (0.1-100 µM) prevented tumor necrosis factor- (TNF-)-induced decrease in viability of SK-N-SH and HCN-1A cells, which was antagonized by 1 µM iberiotoxin, a maxi-K channel blocker. TNF- did not suppress the viability of the U87-MG cell, a phosphatase and tensin homolog deleted from chromosome 10 (PTEN)-null glioblastoma cell, but it did decrease viability of U87-MG cells transfected with expression vectors for the sense PTEN, and this decrease was also prevented by cilostazol. Cilostazol as well as 1,3-dihydro-1-[2-hydroxy-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2H-benzimidazol-2-one (NS-1619) and (3S)(+)-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-(trifluoromethyl)-2H-indole-2-one (BMS 204352), maxi-K channel openers, prevented increased DNA fragmentation evoked by TNF-, which were antagonizable by iberiotoxin. TNF--induced increased PTEN phosphorylation and decreased Akt/cyclic AMP response element-binding protein (CREB) phosphorylation were significantly prevented by cilostazol, those of which were antagonized by both iberiotoxin and paxilline, maxi-K channel blockers. The same results were evident in U87-MG cells transfected with expression vectors for sense PTEN. Cilostazol increases the K⁺ current in SK-N-SH cells by activating maxi-K channels without affecting the ATP-sensitive K⁺ channel. Thus, our results for the first time provide evidence that cilostazol prevents TNF--induced cell death by suppression of PTEN phosphorylation and activation of Akt/CREB phosphorylation via mediation of the maxi-K channel opening.

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