title: Down Regulation of FOXO1 Promotes Cell Proliferation in Cervical Cancer.
abstract: 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'-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.
authors.affiliation: 1. Cancer Genetics Laboratory, Department of Molecular and Human Genetics, Banaras Hindu University, Varanasi-221 005, India;
authors.forename: Shyam Babu
authors.initials: SB
authors.lastname: Prasad
authors.affiliation: 1. Cancer Genetics Laboratory, Department of Molecular and Human Genetics, Banaras Hindu University, Varanasi-221 005, India;
authors.forename: Suresh Singh
authors.initials: SS
authors.lastname: Yadav
authors.affiliation: 1. Cancer Genetics Laboratory, Department of Molecular and Human Genetics, Banaras Hindu University, Varanasi-221 005, India;
authors.forename: Mitali
authors.initials: M
authors.lastname: Das
authors.affiliation: 2. Department of Radiotherapy and Radiation Medicine, Banaras Hindu University, Varanasi-221 005, India;
authors.forename: H B
authors.initials: HB
authors.lastname: Govardhan
authors.affiliation: 3. Department of Obstetrics and Gynaecology, Banaras Hindu University, Varanasi-221 005, India;
authors.forename: Lakshmi Kant
authors.initials: LK
authors.lastname: Pandey
authors.affiliation: 4. Department of Zoology, Mahila Mahavidyalaya; Banaras Hindu University, Varanasi-221 005, India.
authors.forename: Sunita
authors.initials: S
authors.lastname: Singh
authors.affiliation: 2. Department of Radiotherapy and Radiation Medicine, Banaras Hindu University, Varanasi-221 005, India;
authors.forename: Satyajit
authors.initials: S
authors.lastname: Pradhan
authors.affiliation: 1. Cancer Genetics Laboratory, Department of Molecular and Human Genetics, Banaras Hindu University, Varanasi-221 005, India;
authors.forename: Gopeshwar
authors.initials: G
authors.lastname: Narayan
keywords: Apoptosis.; Cervical cancer; FOXO1; LY294002; PI3K/AKT