title: Suppression of NF-kappaB and GSK-3beta is involved in colon cancer cell growth inhibition by the PPAR agonist troglitazone.
abstract: 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.
authors.affiliation: 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
authors.forename: Jung Ok
authors.initials: JO
authors.lastname: Ban
authors.forename: Dong Hoon
authors.initials: DH
authors.lastname: Kwak
authors.forename: Ju Hoon
authors.initials: JH
authors.lastname: Oh
authors.forename: Eun-Jung
authors.initials: EJ
authors.lastname: Park
authors.forename: Min-Chul
authors.initials: MC
authors.lastname: Cho
authors.forename: Ho Seub
authors.initials: HS
authors.lastname: Song
authors.forename: Min Jong
authors.initials: MJ
authors.lastname: Song
authors.forename: Sang Bae
authors.initials: SB
authors.lastname: Han
authors.forename: Dong Cheul
authors.initials: DC
authors.lastname: Moon
authors.forename: Keon Wook
authors.initials: KW
authors.lastname: Kang
authors.forename: Jin Tae
authors.initials: JT
authors.lastname: Hong
mesh_terms: D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division; D002839:Chromans / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000473:pathology*; D024202:Electrophoretic Mobility Shift Assay; D005434:Flow Cytometry; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D047495:PPAR gamma / Q000819:agonists*; D045162:Thiazolidinediones / Q000494:pharmacology*; D000077288:Troglitazone
chemical_list: D002839:Chromans; D016328:NF-kappa B; D047495:PPAR gamma; D045162:Thiazolidinediones; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D000077288:Troglitazone