Augmentation of Sodium Butyrate-induced Apoptosis by Phosphatidylinositol 3-kinase Inhibition in the Human Cervical Cancer Cell-line.
- Author:
Jung Kyu PARK
1
;
Chi Heum CHO
;
Sabarish RAMACHANDRAN
;
So Jin SHIN
;
Sang Hoon KWON
;
Sun Young KWON
;
Soon Do CHA
Author Information
1. Department of Obstetrics and Gynecology, Keimyung University School of Medicine, Daegu, Korea. sdcha@dsmc.or.kr
- Publication Type:Original Article
- Keywords:
Cervical cancer;
Sodium butyrate;
Phosphatidylinositol 3-kinase;
Apoptosis
- MeSH:
Apoptosis*;
Butyric Acid;
Caspase 3;
Caspase 9;
Cell Cycle;
Cell Line;
Cell Survival;
Cervix Uteri;
Cyclin A;
Cyclin B1;
Cyclin D1;
Female;
HeLa Cells;
Histone Deacetylases;
Humans*;
Phosphatidylinositol 3-Kinase*;
Phosphatidylinositols*;
S Phase;
Sodium*;
Uterine Cervical Neoplasms*
- From:Cancer Research and Treatment
2006;38(2):112-117
- CountryRepublic of Korea
- Language:English
-
Abstract:
PURPOSE: Sodium butyrate (NaBT) is principally a histone deacetylase (HDAC) inhibitor, and it has the potential to arrest HPV-positive carcinoma cells at the G1 to S phase transition of the cell cycle. The aim of study was to determine whether phosphatidylinositol 3-kinase (PI3K) inhibition can enhance the inhibitory effect of NaBT on a human cervical cancer cell line (HeLa). MATERIALS AND METHODS: Cervical cancer cells (HeLa) were treated with NaBT alone or in combination with the PI3K inhibitors wortmannin or LY294002. Cell viability analysis and FACS analysis were carried out. The expressions of the cell cycle related proteins were evaluated by Western-blot analysis. RESULTS: Inhibition of PI3K enhanced NaBT-mediated apoptosis and this decreased the HeLa cell viability. Either wortmannin or LY294002, combined with NaBT, enhanced the activation of caspase 3 and caspase 9, and this enhanced the subsequent cleavage of poly (ADP-ribose) polymerase (PARP). Cervical cancer cells were arrested in the subG1 and G2/M phase, as was detected by FACS analysis. NaBT treatment in combination with PI3K inhibitors showed the increased expression of the CDK inhibitors p21(Cip1/Waf1) and p2(7Kip1), in a p53 dependent manner, and also the increased dephosphorylation of Rb whereas there was a reduction in the expression levels of cyclin A, cyclin D1 and cyclin B1. CONCLUSION: The results demonstrate that inhibition of PI3K enhances NaBT-mediated cervical cancer cell apoptosis through the activation of the caspase pathway. Moreover, these findings will support future investigation using the PI3K inhibitors in combination with adjuvant treatment for treating carcinoma of the cervix.
