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PI3K/AKT pathway-mediated regulation of p27(Kip1) is associated with cell cycle arrest and apoptosis in cervical cancer.

AbstractBACKGROUND:
The cyclin-dependent kinase inhibitor p27(Kip1) is known to act as a putative tumor suppressor in several human cancers, including cervical cancer. Down-regulation of p27(Kip1) may occur either through transcription inhibition or through phosphorylation-dependent proteolytic degradation. As yet, the mechanism underlying p27(Kip1) down-regulation and its putative downstream effects on cervical cancer development are poorly understood. Here we assessed the expression and sub-cellular localization of p27(Kip1) and its effects on proliferation, cell cycle progression and (inhibition of) apoptosis in cervical cancer cells.
METHODS:
Primary cervical cancer samples (n = 70), normal cervical tissue samples (n = 30) and cervical cancer-derived cell lines (n = 8) were used to assess the expression of p27(Kip1) and AKT1 by RT-PCR, Western blotting and immunohistochemistry, respectively. The effects of the PI3K inhibitor LY294004 and the proteasome inhibitor MG132 on cervical cancer cell proliferation were investigated using a MTT assay. Apoptosis and cell cycle analyses were carried out using flow cytometry, and sub-cellular p27(Kip1) localization analyses were carried out using immunofluorescence assays.
RESULTS:
We observed p27(Kip1) down-regulation (p = 0.045) and AKT1 up-regulation (p = 0.046) in both the primary cervical cancer samples and the cervical cancer-derived cell lines, compared to the normal cervical tissue samples tested. Treatment of cervical cancer-derived cell lines with the PI3K inhibitor LY294002 resulted in a reduced AKT1 activity. We also observed a dose-dependent inhibition of cell viability after treatment of these cell lines with the proteasome inhibitor MG132. Treatment of the cells with LY294002 resulted in a G1 cell cycle arrest, a nuclear expression of p27(Kip1), and a cytoplasmic p27(Kip1) accumulation after subsequent treatment with MG132. Additionally, we found that the synergistic effect of MG132 and LY294002 resulted in a sub-G1 cell cycle arrest and apoptosis induction through poly (ADP-ribose) polymerase (PARP) cleavage.
CONCLUSION:
Our data suggest that p27(Kip1) down-regulation in cervical cancer cells is primarily regulated through PI3K/AKT-mediated proteasomal degradation. The observed synergistic effect of the MG132 and LY294002 inhibitors may form a basis for the design of novel cervical cancer therapies.
AuthorsShyam Babu Prasad, Suresh Singh Yadav, Mitali Das, Arusha Modi, Soni Kumari, Lakshmi Kant Pandey, Sunita Singh, Satyajit Pradhan, Gopeshwar Narayan
JournalCellular oncology (Dordrecht) (Cell Oncol (Dordr)) Vol. 38 Issue 3 Pg. 215-25 (Jun 2015) ISSN: 2211-3436 [Electronic] Netherlands
PMID25821107 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

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