Induction of endoplasmic reticulum stress response by the indole-3-carbinol cyclic tetrameric derivative CTet in human breast cancer cell lines.
Induction of endoplasmic reticulum stress response by the indole-3-carbinol cyclic tetrameric derivative CTet in human breast cancer cell lines.
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DOI：
10.1371/journal.pone.0043249
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Magnani M
中科院分区：
文献类型：
--
作者：
Galluzzi L;De Santi M;Crinelli R;De Marco C;Zaffaroni N;Duranti A;Brandi G;Magnani M
吲哚-3-甲醇及其代谢产物被认为是有前途的化学预防和抗癌药物。以前我们已经表明，吲哚-3-甲醇环状四聚体衍生物CTet诱导自噬和抑制细胞增殖，通过抑制Akt活性和过度表达的p21/CDKN 1A和GADD 45 A，在雌激素受体阳性（MCF-7）和三阴性（MDA-MB-231）乳腺癌细胞系。在本研究中，我们进一步描述了自噬反应，并研究了CTet调节这些事件的机制。基因表达微阵列数据的分析和随后通过定量实时PCR的确认显示，CTet能够在MCF-7和MDA-MB-231细胞系中诱导参与内质网（ER）应激反应（例如DDIT 3/CHOP、CHAC 1、ATF 3、HSPA 5/BiP/GRP 78、CEBPB、ASNS）和自噬（例如MAP 1 LC 3B）的关键信号分子的上调。此外，Xbp-1剪接的监测证实了CTet处理后IRE 1/Xbp-1 ER应激反应分支的激活。通过ATG 5基因沉默和AVO形成的药理学抑制进一步研究了自噬过程（已知由ER应激诱导）的作用。CTet显示诱导自噬相关的细胞死亡。此外，CTet处理的细胞与Hoechst/PI染色揭示了坏死过程的存在，没有凋亡的证据。ER应激反应被确定为CTet在乳腺癌细胞中起作用的主要上游分子机制，CTet通过该机制在乳腺癌细胞应答和三阴性乳腺癌细胞中起作用。由于其在肿瘤发生发展中的重要作用，内质网应激是肿瘤治疗的潜在靶点。CTet诱导ER应激反应并随后激活肿瘤细胞中的死亡程序的能力证实了该分子作为有前途的抗癌剂。
Indole-3-carbinol and its metabolic products are considered promising chemopreventive and anticancer agents. Previously we have shown that the indole-3-carbinol cyclic tetrameric derivative CTet induces autophagy and inhibits cell proliferation via inhibition of Akt activity and overexpression of p21/CDKN1A and GADD45A, in both estrogen receptor-positive (MCF-7) and triple negative (MDA-MB-231) breast cancer cell lines. In the present study, we further characterize the autophagic response and investigate the mechanism through which CTet regulates these events. Analysis of gene expression microarray data and subsequent confirmation by quantitative real-time PCR, showed that CTet is able to induce up-regulation of key signaling molecules involved in endoplasmic reticulum (ER) stress response (e.g. DDIT3/CHOP, CHAC1, ATF3, HSPA5/BiP/GRP78, CEBPB, ASNS) and autophagy (e.g. MAP1LC3B), in both MCF-7 and MDA-MB-231 cell lines. Moreover, the monitoring of Xbp-1 splicing confirmed the activation of IRE1/Xbp-1 ER stress response branch after CTet treatment. The role of autophagic processes (known to be induced by ER stress) was investigated further through ATG5 gene silencing and pharmacological inhibition of AVOs formation. CTet was shown to induce an autophagy-related cell death. Moreover, CTet-treated cells stained with Hoechst/PI revealed the presence of necrotic processes without evidence of apoptosis. The ER stress response was identified as the main upstream molecular mechanism through which CTet acts in both hormone-responsive and triple-negative breast cancer cells. Because of its important role in cancer development, ER stress is a potential target in cancer therapy. The abiltiy of CTet to induce ER stress response and subsequently activate a death program in tumor cells confirms this molecule as a promising anticancer agent.
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