1,1-bis(3′-indolyl)-1-(p-substituted phenyl)methanes inhibit ovarian cancer cell growth through peroxisome proliferator-activated receptor-dependent and independent pathways
1,1-bis(3′-indolyl)-1-(p-substituted phenyl)methanes inhibit ovarian cancer cell growth through peroxisome proliferator-activated receptor-dependent and independent pathways
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DOI：
10.1158/1535-7163.mct-06-0184
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发表时间：
2006-09-01
影响因子：
5.7
通讯作者：
Safe, Stephen
中科院分区：
文献类型：
--
作者：
Lei, Ping;Abdelrahim, Maen;Safe, Stephen
1,1-双(3'-吲哚基)-1-(对叔丁基苯基)甲烷(DIM-C-pPhtBu)是一种过氧化物酶体增殖物激活受体γ(PPARγ)激动剂，用该化合物(5μmol/L)处理SKOV3卵巢癌细胞可抑制细胞增殖，而高达15μmol/L的罗格列酮对细胞生长没有影响。 DIM-C-pPhtBu 还抑制 Go-G 至 S 期细胞周期进程，这部分与细胞周期蛋白依赖性激酶抑制剂 p21 的 PPAR γ 依赖性诱导有关。 DIM-C-pPhtBu 诱导 PPAR γ 依赖性细胞周期蛋白 D1 下调，因此我们进一步研究了受体依赖性途径的激活。 DIM-C-pPhtBu 还诱导 SKOV3 细胞凋亡，这与葡萄糖相关蛋白 78 的诱导有关，该蛋白通常在内质网 (ER) 应激期间作为未折叠蛋白反应的一部分而上调。在用 DIM-C-pPhtBu 处理的其他卵巢癌细胞系中也观察到 ER 应激的激活。此外，DIM-C-pPhtBu通过ER应激和c-jun NH2末端激酶依赖性途径诱导CCAAT/增强子结合蛋白同源蛋白，并且CCAAT/增强子结合蛋白同源蛋白激活死亡受体5和细胞凋亡的外在途径。这些结果表明，DIM-C-pPhtBu通过PPARγ依赖性和PPARγ非依赖性途径抑制卵巢癌细胞的生长并诱导细胞凋亡，这种复杂的作用机制将有利于这些化合物用于治疗卵巢癌的未来临床开发。
1,1-Bis(3'-indolyl)-1-(p-t-butylphenyl)methane (DIM-C-pPhtBu) is a peroxisome proliferator-activated receptor gamma (PPAR gamma) agonist, and treatment of SKOV3 ovarian cancer cells with this compound (5 mu mol/L) inhibits cell proliferation, whereas up to 15 mu mol/L rosiglitazone had no effect on cell growth. DIM-C-pPhtBu also inhibits Go-G, to S phase cell cycle progression and this is linked, in part, to PPAR gamma-dependent induction of the cyclin-dependent kinase inhibitor p21. DIM-C-pPhtBu induces PPAR gamma-independent down-regulation of cyclin D1 and we therefore further investigated activation of receptor-independent pathways. DIM-C-pPhtBu also induced apoptosis in SKOV3 cells and this was related to induction of glucose-related protein 78, which is typically up-regulated as part of the unfolded protein response during endoplasmic reticulum (ER) stress. Activation of ER stress was also observed in other ovarian cancer cell lines treated with DIM-C-pPhtBu. In addition, DIM-C-pPhtBu induced CCAAT/enhancer binding protein homologous protein through both ER stress and c-jun NH2-terminal kinase-dependent pathways, and CCAAT/enhancer binding protein homologous protein activated death receptor 5 and the extrinsic pathway of apoptosis. These results show that DIM-C-pPhtBu inhibits growth and induces apoptosis in ovarian cancer cells through both PPAR gamma-dependent and PPAR gamma-independent pathways, and this complex mechanism of action will be advantageous for future clinical development of these compounds for treatment of ovarian cancer.