Augmentation of Sodium Butyrate-induced Apoptosis by Phosphatidylinositol 3-kinase Inhibition in the Human Cervical Cancer Cell-line

다국어 초록 (Multilingual Abstract)

Purpose: Sodium butyrate (NaBT) is principally a histonedeacetylase (HDAC) inhibitor, and it has the potentialto arrest HPV-positive carcinoma cells at the G1 toS phase transition of the cell cycle. The aim of study wasto determine whether phosphatidylinositol 3-kinase(PI3K) inhibition can enhance the inhibitory effect ofNaBT on a human cervical cancer cell line (HeLa).Materials and Methods: Cervical cancer cells (HeLa)were treated with NaBT alone or in combination with thePI3K inhibitors wortmannin or LY294002. Cell viabilityanalysis and FACS analysis were carried out. The expressionsof the cell cycle related proteins were evaluatedby Western-blot analysis.Results: Inhibition of PI3K enhanced NaBT-mediatedapoptosis and this decreased the HeLa cell viability.Either wortmannin or LY294002, combined with NaBT,enhanced the activation of caspase 3 and caspase 9, andthis enhanced the subsequent cleavage of poly (ADPribose)polymerase (PARP). Cervical cancer cells werearrested in the subG1 and G2/M phase, as was detectedby FACS analysis. NaBT treatment in combination withPI3K inhibitors showed the increased expression of theCDK inhibitors p21Cip1/Waf1 and p27Kip1, in a p53 dependentmanner, and also the increased dephosphorylation of Rbwhereas there was a reduction in the expression levelsof cyclin A, cyclin D1 and cyclin B1.Conclusion: The results demonstrate that inhibition ofPI3K enhances NaBT-mediated cervical cancer cell apoptosisthrough the activation of the caspase pathway.Moreover, these findings will support future investigationusing the PI3K inhibitors in combination with adjuvanttreatment for treating carcinoma of the cervix. (CancerRes Treat. 2006;38:112-117)

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