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Research ArticleCELLULAR AND MOLECULAR

Cilostazol Prevents Tumor Necrosis Factor-α-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

Ki Whan Hong, Ki Young Kim, Hwa Kyoung Shin, Jeong Hyun Lee, Jae Moon Choi, Yong-Geun Kwak, Chi Dae Kim, Won Suk Lee and Byung Yong Rhim
Journal of Pharmacology and Experimental Therapeutics September 2003, 306 (3) 1182-1190; DOI: https://doi.org/10.1124/jpet.103.052365
Ki Whan Hong
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Ki Young Kim
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Hwa Kyoung Shin
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Jeong Hyun Lee
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Jae Moon Choi
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Yong-Geun Kwak
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Chi Dae Kim
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Won Suk Lee
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Byung Yong Rhim
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Abstract

This study examines the signaling mechanism by which cilostazol prevents neuronal cell death. Cilostazol (∼0.1-100 μM) prevented tumor necrosis factor-α (TNF-α)-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-α 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-α, which were antagonizable by iberiotoxin. TNF-α-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-α-induced cell death by suppression of PTEN phosphorylation and activation of Akt/CREB phosphorylation via mediation of the maxi-K channel opening.

Footnotes

  • This study was supported by funds from the Research Institute of Genetic Engineering (Pusan National University) and the Research Funds from Korea Otsuka Pharmaceutical Co. Ltd.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • DOI: 10.1124/jpet.103.052365.

  • ABBREVIATIONS: PTEN, phosphatase and tensin homolog deleted from chromosome 10; PI(3,4,5)P3, phosphatidylinositol 3,4,5-triphosphate; PI3-K, phosphatidylinositol 3-kinase; PI(3,4)P2, phosphatidylinositol 3,4-diphosphate; CREB, cyclic AMP response element-binding protein; p-PTEN, phosphorylated PTEN; p-Akt and p-CREB, phosphorylated Akt and CREB; sPTEN, transfected with expression vectors for sense PTEN; MEM, minimal essential medium; bp, base pair(s); MTT, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide; NS-1619, 1,3-dihydro-1-[2-hydroxy-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2H-benzimidazol-2-one; BMS 204352, (3S)-(+)-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-(trifluoromethyl)-2H-indole-2-one.

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Journal of Pharmacology and Experimental Therapeutics: 306 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 306, Issue 3
1 Sep 2003
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Research ArticleCELLULAR AND MOLECULAR

Cilostazol Prevents Tumor Necrosis Factor-α-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

Ki Whan Hong, Ki Young Kim, Hwa Kyoung Shin, Jeong Hyun Lee, Jae Moon Choi, Yong-Geun Kwak, Chi Dae Kim, Won Suk Lee and Byung Yong Rhim
Journal of Pharmacology and Experimental Therapeutics September 1, 2003, 306 (3) 1182-1190; DOI: https://doi.org/10.1124/jpet.103.052365

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Research ArticleCELLULAR AND MOLECULAR

Cilostazol Prevents Tumor Necrosis Factor-α-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

Ki Whan Hong, Ki Young Kim, Hwa Kyoung Shin, Jeong Hyun Lee, Jae Moon Choi, Yong-Geun Kwak, Chi Dae Kim, Won Suk Lee and Byung Yong Rhim
Journal of Pharmacology and Experimental Therapeutics September 1, 2003, 306 (3) 1182-1190; DOI: https://doi.org/10.1124/jpet.103.052365
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