PT  - JOURNAL ARTICLE
AU  - Kim, Ki Young
AU  - Shin, Hwa Kyoung
AU  - Lee, Jeong Hyun
AU  - Kim, Chi Dae
AU  - Lee, Won Suk
AU  - Rhim, Byung Yong
AU  - Shin, Yung Woo
AU  - Hong, Ki Whan
TI  - Cilostazol Enhances Casein Kinase 2 Phosphorylation and Suppresses Tumor Necrosis Factor-α-Induced Increased Phosphatase and Tensin Homolog Deleted from Chromosome 10 Phosphorylation and Apoptotic Cell Death in SK-N-SH Cells
AID  - 10.1124/jpet.103.058768
DP  - 2004 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 97--104
VI  - 308
IP  - 1
4099  - http://jpet.aspetjournals.org/content/308/1/97.short
4100  - http://jpet.aspetjournals.org/content/308/1/97.full
SO  - J Pharmacol Exp Ther2004 Jan 01; 308
AB  - This study shows the signaling pathway by which cilostazol suppresses tumor necrosis factor-α (TNF-α)-induced the phosphatase and tensin homolog deleted from chromosome 10 (PTEN) phosphorylation and apoptosis via casein kinase 2 (CK2) phosphorylation in the SK-N-SH cells (neuroblastoma cells). Cilostazol (10 μM) fully restored cell proliferation with suppression of DNA fragmentation induced by TNF-α and emodin, a CK2 inhibitor, which were antagonized by iberiotoxin, a maxi-K channel blocker. Under application of TNF-α or emodin, increased PTEN phosphorylation and decreased phosphorylation of CK2/Akt/cyclic AMP response element-binding protein (CREB), and CK2 activity were significantly reversed by cilostazol (∼1-100 μM), all of which were antagonized by iberiotoxin. 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-indol-2-one (BMS 204352) maxi-K channel openers significantly elevated CK2 activities that were reversible by iberiotoxin. SK-N-SH cells treated with antisense CK2 oligodeoxynucleotide showed a prominent DNA fragmentation with little responsiveness to TNF-α in the phosphorylation of PTEN, indicative of the essential role of p-CK2/CK2 in cell proliferation, and the decreased cell viability of these cells was not restored by cilostazol. It is suggested that the action of cilostazol promoting cell survival is ascribed to the maxi-K channel opening-coupled up-regulation of CK2 phosphorylation and down-regulation of PTEN phosphorylation with resultant increased phosphorylation of Akt and CREB. The American Society for Pharmacology and Experimental Therapeutics