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CELLULAR AND MOLECULAR

Cilostazol Enhances Casein Kinase 2 Phosphorylation and Suppresses Tumor Necrosis Factor--Induced Increased Phosphatase and Tensin Homolog Deleted from Chromosome 10 Phosphorylation and Apoptotic Cell Death in SK-N-SH Cells

Department of Pharmacology and Internal Medicine (Y.W.S.), College of Medicine (K.Y.K., H.K.S., J.H.L., C.D.K., W.S.L., B.Y.R., K.W.H.), Pusan National University, Busan, Korea

This study shows the signaling pathway by which cilostazol suppresses tumor necrosis factor- (TNF-)-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- and emodin, a CK2 inhibitor, which were antagonized by iberiotoxin, a maxi-K channel blocker. Under application of TNF- 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- 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.

Address correspondence to: Dr. Ki Whan Hong, Department of Pharmacology, College of Medicine, Pusan National University, 10 Ami-Dong, 1-Ga, Seo-Gu, Busan 602-739, Korea. E-mail: kwhong{at}pusan.ac.kr

This article has been cited by other articles:

				J. H. Lee, K. Y. Kim, Y.-K. Lee, S. Y. Park, C. D. Kim, W. S. Lee, B. Y. Rhim, and K. W. Hong Cilostazol Prevents Focal Cerebral Ischemic Injury by Enhancing Casein Kinase 2 Phosphorylation and Suppression of Phosphatase and Tensin Homolog Deleted from Chromosome 10 Phosphorylation in Rats J. Pharmacol. Exp. Ther., March 1, 2004; 308(3): 896 - 903. [Abstract] [Full Text] [PDF]