Vitamin K3 induces cell cycle arrest and cell death by inhibiting Cdc25 phosphatase.
Our early reports have indicated that vitamin K3 (VK3) exerts antitumour activity by inhibiting Cdk1 activity and overexpressing the c-myc gene to induce an apoptotic cell death. In the present study, we investigated the effect of VK3 on Cdc25 phosphatase, a Cdk1 activator and c-Myc-downstream protein. Increased protein level but decreased activity of Cdc25A phosphatase was found in cervical carcinoma SiHa cells treated with VK3 for 1 h and allowed to recover for 8, 24, 30 or 45 h. The binding of VK3 to Cdc25 phosphatase was proven by incubating [methyl-3H]-VK3 with the 27 kDa-catalytic domain of Cdc25A phosphatase at 35 degrees C for 2 h. We found that VK3 inhibited cyclin E expression at late G1 phase and cyclin A at G1/S transition of the aphidicolin-synchronised SiHa cells, but had no effect on Cdk2 and Cdk4. The inhibition of cyclins E and A expression was associated with cell cycle progression delay in the S phase. These results indicate that binding of VK3 to the catalytic domain of Cdc25 phosphatase results in the formation of inactive, hyperphosphorylated Cdk1 that subsequently induces cell cycle arrest, leading to cell death. These findings suggest a possible therapeutic strategy, with VK3 serving as a potential antagonist to tumours expressing high levels of proteins containing cysteine such as oncogenic Cdc25A phosphatase.
Wu
F Y
FY
Division of Cancer Research, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, R.O.C.
Sun
T P
TP
D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors; D005260:Female; D018816:Genes, cdc / Q000502:physiology; D006801:Humans; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000473:pathology; D014812:Vitamin K / Q000627:therapeutic use*
D018797:Cell Cycle Proteins; D014812:Vitamin K; D010749:Phosphoprotein Phosphatases