College of Pharmacy and Medical Research Center, Chungbuk National University, 48 Gaesin-dong, Heungduk-gu, Cheongju, Chungbuk 361-763, Republic of Korea.
Chem Biol Interact. 2010 Oct 6;188(1):75-85. doi: 10.1016/j.cbi.2010.06.001. Epub 2010 Jun 9.
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.
过氧化物酶体增殖物激活受体（PPAR）-γ激动剂，如曲格列酮、吡格列酮和噻唑烷二酮，已被证明可诱导人结肠癌细胞凋亡。然而，PPARγ激动剂诱导结肠癌细胞凋亡的分子机制尚不清楚。糖原合酶激酶-3β（GSK-3β）是核因子-κB（NF-κB）激活所必需的元素，NF-κB在肿瘤细胞中存活信号的转导中起着关键作用。为了研究 PPARγ激动剂诱导结肠癌细胞凋亡的机制，我们研究了曲格列酮（0-16μM）对 GSK-3β和 NF-κB 激活的影响。我们的研究表明，曲格列酮抑制结肠癌细胞生长的作用与 NF-κB 活性和 GSK-3β表达的剂量依赖性抑制有关。曲格列酮处理后，细胞被阻滞在 G0/G1 期，随后诱导凋亡，同时降低 G0/G1 期调节蛋白的表达；Cdk2、Cdk4、cyclin B1、D1 和 E 以及抗凋亡蛋白 Bcl-2，同时增加促凋亡相关蛋白的表达；Caspase-3、Caspase-9 和 Bax。GSK-3β 的瞬时转染恢复了曲格列酮诱导的细胞生长抑制和 NF-κB 失活。相反，曲格列酮与 GSK-3β抑制剂（AR-a014418）或 GSK-3β 的 siRNA 共同处理，显著增强了曲格列酮对 NF-κB 活性、癌细胞生长以及 G0/G1 期调节蛋白和促凋亡调节蛋白表达的抑制作用。这些结果表明，PPARγ 激动剂曲格列酮通过抑制 GSK-3β 活性抑制 NF-κB 的活性，从而抑制结肠癌细胞的生长。
