| Suppression of NF-kappaB and GSK-3beta is involved in colon cancer cell growth inhibition by the PPAR agonist troglitazone. | |
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MedLine Citation:
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PMID: 20540935 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Peroxisome proliferator-activated receptor (PPAR)-gamma agonists such as troglitazone, pioglitazone and thiazolidine have been shown to induce apoptosis in human colon cancer cells. The molecular mechanism of PPARgamma agonist-induced apoptosis of colon cancer cells, however, is not clear. Glycogen synthase kinase-3beta (GSK-3beta) is an indispensable element for the activation of nuclear factor-kappa B (NF-kappaB) which plays a critical role in the mediation of survival signals in cancer cells. To investigate the mechanisms of PPARgamma agonist-induced apoptosis of colon cancer cells, we examined the effect of troglitazone (0-16muM) on the activation of GSK-3beta and NF-kappaB. Our study showed that the inhibitory effect of troglitazone on colon cancer cell growth was associated with inhibition of NF-kappaB activity and GSK-3beta expression in a dose-dependent manner. Cells were arrested in G(0)/G(1) phase followed by the induction of apoptosis after treatment of troglitazone with concomitant decrease in the expression of the G(0)/G(1) phase regulatory proteins; Cdk2, Cdk4, cyclin B1, D1, and E as well as in the anti-apoptosis protein Bcl-2 along with an increase in the expression of the pro-apoptosis-associated proteins; Caspase-3, Caspase-9 and Bax. Transient transfection of GSK-3beta recovered troglitazone-induced cell growth inhibition and NF-kappaB inactivation. In contrast, co-treatment of troglitazone with a GSK-3beta inhibitor (AR-a014418) or siRNA against GSK-3beta, significantly augmented the inhibitory effect of troglitazone on the NF-kappaB activity, the cancer cell growth and on the expression of G(0)/G(1) phase regulatory proteins and pro-apoptosis regulatory proteins. These results suggest that the PPARgamma agonist, troglitazone, inhibits colon cancer cell growth via inactivation of NF-kappaB by suppressing GSK-3beta activity. |
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Authors:
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Jung Ok Ban; Dong Hoon Kwak; Ju Hoon Oh; Eun-Jung Park; Min-Chul Cho; Ho Seub Song; Min Jong Song; Sang Bae Han; Dong Cheul Moon; Keon Wook Kang; Jin Tae Hong |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-06-09 |
Journal Detail:
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Title: Chemico-biological interactions Volume: 188 ISSN: 1872-7786 ISO Abbreviation: Chem. Biol. Interact. Publication Date: 2010 Oct |
Date Detail:
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Created Date: 2010-08-31 Completed Date: 2010-10-04 Revised Date: 2011-11-02 |
Medline Journal Info:
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Nlm Unique ID: 0227276 Medline TA: Chem Biol Interact Country: Ireland |
Other Details:
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Languages: eng Pagination: 75-85 Citation Subset: IM |
Copyright Information:
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Copyright 2010 Elsevier Ireland Ltd. All rights reserved. |
Affiliation:
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College of Pharmacy and Medical Research Center, Chungbuk National University, 48 Gaesin-dong, Heungduk-gu, Cheongju, Chungbuk 361-763, Republic of Korea. okimel@hanmail.net |
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| MeSH Terms | |
Descriptor/Qualifier:
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Cell Cycle
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drug effects Cell Division Chromans / pharmacology* Colonic Neoplasms / pathology* Electrophoretic Mobility Shift Assay Flow Cytometry Glycogen Synthase Kinase 3 / antagonists & inhibitors* Humans NF-kappa B / antagonists & inhibitors* PPAR gamma / agonists* Thiazolidinediones / pharmacology* |
| Chemical | |
Reg. No./Substance:
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0/Chromans; 0/NF-kappa B; 0/PPAR gamma; 0/Thiazolidinediones; 97322-87-7/troglitazone; EC 2.7.11.1/glycogen synthase kinase 3 beta; EC 2.7.11.26/Glycogen Synthase Kinase 3 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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