Down Regulation of FOXO1 Promotes Cell Proliferation in Cervical Cancer

作者：Prasad Shyam Babu; Yadav Suresh Singh; Das Mitali; Govardhan H B; Pandey Lakshmi Kant; Singh Sunita; Pradhan Satyajit; Narayan Gopeshwar^*

来源：Journal of Cancer, 2014, 5(8): 655-662.

DOI：10.7150/jca.6554

• Cervical cancer
• PI3K/AKT
• FOXO1
• LY294002
• Apoptosis

The Forkhead transcription factor FOXO1, an important downstream target of phosphatidylinositol-3-kinase (PI3K)/AKT signaling pathway, regulates cellular homeostasis by maintaining cell proliferation, apoptosis and viability in normal cells. Though, the function and regulation of FOXO1 is well documented in many cancers, the molecular mechanism of its regulation in cervical cancer is largely unknown. In the present study we have investigated the role of PI3K inhibition on FOXO1 regulation. Expression profiling of primary tumors and cell lines show over expression of PIK3CA and AKT1; and down regulation of FOXO1. Lack of FOXO1 promoter methylation and inability of hypomethylating drug 5-Aza-2%26apos;-deoxycytidine and HDAC inhibitor trichostatin A to reactivate FOXO1 expression suggest that loss of FOXO1 expression is due to mechanisms other than promoter methylation/acetylation. Inhibition of PI3K by LY294002 decreased the level of p-AKT1 and activated FOXO1 transcription factor. We demonstrate that activation of FOXO1 induces apoptosis, cell proliferation arrest, and decreased cell viability in cervical cancer cell lines. Our data suggest that frequent down regulation of FOXO1 and its functional inactivation may be due to post-translational modifications in cervical cancer. Together, these observations suggest that activation of FOXO1 and its nuclear sequestration is critical in the regulation of cell proliferation, cell viability and apoptosis in cervical cancer. Hence, PI3K/AKT pathway may be a potential molecular target for cervical cancer therapy.

• 出版日期2014