Cancer Res Treat.  2006 Apr;38(2):112-117.

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

Affiliations
  • 1Department of Obstetrics and Gynecology, Keimyung University School of Medicine, Daegu, Korea. sdcha@dsmc.or.kr
  • 2Department of Pathology, Keimyung University School of Medicine, Daegu, Korea.

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.

Keyword

Cervical cancer; Sodium butyrate; Phosphatidylinositol 3-kinase; Apoptosis

MeSH Terms

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*
Butyric Acid
Caspase 3
Caspase 9
Cyclin A
Cyclin B1
Cyclin D1
Histone Deacetylases
Phosphatidylinositol 3-Kinase
Phosphatidylinositols
Sodium
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