Cilostazol enhances casein kinase 2 phosphorylation and suppresses tumor necrosis factor-alpha-induced increased phosphatase and tensin homolog deleted from chromosome 10 phosphorylation and apoptotic cell death in SK-N-SH cells.
This study shows the signaling pathway by which cilostazol suppresses tumor necrosis factor-alpha (TNF-alpha)-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 microM) fully restored cell proliferation with suppression of DNA fragmentation induced by TNF-alpha and emodin, a CK2 inhibitor, which were antagonized by iberiotoxin, a maxi-K channel blocker. Under application of TNF-alpha 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 (approximately 1-100 microM), 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-alpha 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.
College of Medicine, Pusan National University, Busan, Korea.
Ki Young
KY
Kim
Hwa Kyoung
HK
Shin
Jeong Hyun
JH
Lee
Chi Dae
CD
Kim
Won Suk
WS
Lee
Byung Yong
BY
Rhim
Yung Woo
YW
Shin
Ki Whan
KW
Hong
D017209:Apoptosis / Q000502:physiology*; D001562:Benzimidazoles / Q000494:pharmacology; D047390:Casein Kinase II; D016923:Cell Death; D002879:Chromosomes, Human, Pair 10; D000077407:Cilostazol; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008840:Microfilament Proteins / Q000737:chemistry / Q000378:metabolism*; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D000070876:Tensins; D013777:Tetrazoles / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology
C424388:BMS204352; D001562:Benzimidazoles; D017362:Cyclic AMP Response Element-Binding Protein; D007211:Indoles; D008840:Microfilament Proteins; D011518:Proto-Oncogene Proteins; D000070876:Tensins; D013777:Tetrazoles; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; D014665:Vasodilator Agents; C086491:NS 1619; C494918:AKT1 protein, human; D047390:Casein Kinase II; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D000077407:Cilostazol