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Co-depletion of cathepsin B and uPAR induces G0/G1 arrest in glioma via FOXO3a mediated p27 upregulation

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Title: Co-depletion of cathepsin B and uPAR induces G0/G1 arrest in glioma via FOXO3a mediated p27 upregulation
Author(s): Gopinath, Sreelatha; Malla, Rama Rao; Gondi, Christopher S.; Alapati, Kiranmai; Fassett, Daniel; Klopfenstein, Jeffrey D.; Dinh, Dzung H.; Gujrati, Meena; Rao, Jasti S.
Subject(s): cathepsin B glioma
Abstract: BACKGROUND: Cathepsin B and urokinase plasminogen activator receptor (uPAR) are both known to be overexpressed in gliomas. Our previous work and that of others strongly suggest a relationship between the infiltrative phenotype of glioma and the expression of cathepsin B and uPAR. Though their role in migration and adhesion are well studied the effect of these molecules on cell cycle progression has not been thoroughly examined. METHODOLOGY/PRINCIPAL FINDINGS: Cathepsin B and uPAR single and bicistronic siRNA plasmids were used to downregulate these molecules in SNB19 and U251 glioma cells. FACS analysis and BrdU incorporation assay demonstrated G0/G1 arrest and decreased proliferation with the treatments, respectively. Immunoblot and immunocyto analysis demonstrated increased expression of p27(Kip1) and its nuclear localization with the knockdown of cathepsin B and uPAR. These effects could be mediated by alphaVbeta3/PI3K/AKT/FOXO pathway as observed by the decreased alphaVbeta3 expression, PI3K and AKT phosphorylation accompanied by elevated FOXO3a levels. These results were further confirmed with the increased expression of p27(Kip1) and FOXO3a when treated with Ly294002 (10 microM) and increased luciferase expression with the siRNA and Ly294002 treatments when the FOXO binding promoter region of p27(Kip1) was used. Our treatment also reduced the expression of cyclin D1, cyclin D2, p-Rb and cyclin E while the expression of Cdk2 was unaffected. Of note, the Cdk2-cyclin E complex formation was reduced significantly. CONCLUSION/SIGNIFICANCE: Our study indicates that cathepsin B and uPAR knockdown induces G0/G1 arrest by modulating the PI3K/AKT signaling pathway and further increases expression of p27(Kip1) accompanied by the binding of FOXO3a to its promoter. Taken together, our findings provide molecular mechanism for the G0/G1 arrest induced by the downregulation of cathepsin B and uPAR in SNB19 and U251 glioma cells.
Issue Date: 2010-07-22
Publisher: Public Library of Science
Citation Info: Gopinath, S., Malla, R. R., Gondi, C. S., Alapati, K., Fassett, D., Klopfenstein, J. D., Dinh, D. H., Gujrati, M., & Rao, J. S. 2010. Co-depletion of cathepsin B and uPAR induces G0/G1 arrest in glioma via FOXO3a mediated p27 upregulation. PLoS One, 5(7): e11668. DOI: 10.1371/journal.pone.0011668.
Type: Article
Description: 2010 Gopinath et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The original source for this publication is at Public Library of Science. DOI: 10.1371/journal.pone.0011668
URI: http://hdl.handle.net/10027/7711
ISSN: 1923-6203
Sponsor: This research was supported by a grant from National Institutes of Health, CA116708 (to J.S.R.) The contents are solely the responsibility of the authors and do not necessarily represent the official views of NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Date Available in INDIGO: 2011-05-27
 

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