Rottlerin induces pro-apoptotic endoplasmic reticulum stress through the protein kinase C-δ-independent pathway in human colon cancer cells
Rottlerin induces pro-apoptotic endoplasmic reticulum stress through the protein kinase C-δ-independent pathway in human colon cancer cells
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DOI：
10.1007/s10495-008-0264-z
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发表时间：
2008-11-01
期刊：
影响因子：
7.2
通讯作者：
Kwon, Taeg Kyu
中科院分区：
文献类型：
--
作者：
Lim, Jun Hee;Park, Jong-Wook;Kwon, Taeg Kyu
Rottlerin 是一种据报道为 PKC δ 选择性抑制剂的化合物，已被证明可诱导人类癌细胞系生长停滞或凋亡。在我们的研究中，rottlerin 剂量依赖性地诱导结肠癌细胞凋亡。研究发现，用 Rottlerin 处理 HT29 人类结肠癌细胞可诱导许多特征性 ER 应激标记物；真核起始因子 2 α (eIF-2 α) 的磷酸化、内质网应激特异性 XBP1 剪接以及葡萄糖调节蛋白 (GRP)-78 和 CCAAT/增强子结合蛋白同源蛋白 (CHOP) 的上调。然而，通过 siRNA 抑制 PKC δ 表达或过度表达 WT-PKC δ 和 DN-PKC δ 并不能消除 Rottlerin 介导的 CHOP 诱导。这些结果表明 Rottlerin 通过 PKC δ 独立途径诱导 CHOP 上调。此外，使用 CHOP siRNA 下调 CHOP 表达可减弱 Rottlerin 诱导的细胞凋亡。综上所述，本研究提供了强有力的证据来支持 ER 应激反应在介导 Rottlerin 诱导的细胞凋亡中的重要作用。
Rottlerin, a compound reported to be a PKC delta-selective inhibitor, has been shown to induce growth arrest or apoptosis of human cancer cell lines. In our study, rottlerin dose-dependently induced apoptotic cell death in colon carcinoma cells. Treatment of HT29 human colon carcinoma cells with rottlerin was found to induce a number of signature ER stress markers; phosphorylation of eukaryotic initiation factor-2 alpha (eIF-2 alpha), ER stress-specific XBP1 splicing, and up-regulation of glucose-regulated protein (GRP)-78 and CCAAT/enhancer-binding protein-homologous protein (CHOP). However, suppression of PKC delta expression by siRNA or overexpression of WT-PKC delta and DN-PKC delta did not abrogate the rottlerin-mediated induction of CHOP. These results suggest that rottlerin induces up-regulation of CHOP via PKC delta-independent pathway. Furthermore, down-regulation of CHOP expression using CHOP siRNA attenuated rottlerin-induced apoptosis. Taken together, the present study thus provides strong evidence to support an important role of ER stress response in mediating the rottlerin-induced apoptosis.