Smac deficiency affects endoplasmic reticulum stress-induced apoptosis in human colon cancer cells.
Smac deficiency affects endoplasmic reticulum stress-induced apoptosis in human colon cancer cells.
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DOI：
10.4255/mcpharmacol.09.04
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发表时间：
2009
期刊：
影响因子：
--
通讯作者：
Sheikh MS
中科院分区：
文献类型：
--
作者：
He Q;Shi J;Jones S;An J;Liu Y;Huang Y;Sheikh MS
毒胡萝卜素（TG）是一种倍半萜内酯，可抑制内质网（ER）钙ATP酶，破坏钙稳态，从而诱导ER应激。我们以前曾报道TG通过激活死亡受体5（DR 5）和内源性途径诱导细胞凋亡。第二类脑源性激活因子（Smac）是一种重要的细胞凋亡调节因子，通过拮抗凋亡抑制因子（IAP）诱导caspase的激活。在这项研究中，我们已经利用Smac熟练和缺陷的人结肠癌细胞研究ER应激诱导的细胞凋亡过程中Smac缺陷的影响。我们的研究结果表明，Smac缺陷显着影响ER应激诱导的人结肠癌细胞凋亡。例如，ER应激诱导剂TG上调DR 5，并激活Smac-proficient细胞中的半胱天冬酶3、9和8。在Smac缺陷细胞中，尽管TG诱导的DR 5上调不受影响，但半胱天冬酶3、9和8的活化受到影响。Smac缺陷也影响TG诱导的细胞色素c从线粒体释放到细胞质中，这表明Smac和细胞色素c之间存在潜在的串扰。因此，我们的研究结果表明，ER应激诱导的细胞凋亡也参与Smac在人结肠癌细胞中的凋亡信号转导，并且Smac和细胞色素c之间的潜在反馈信号似乎调节细胞凋亡的内在途径。
Thapsigargin (TG) is a sesquiterpen lactone that inhibits the endoplasmic reticulum (ER) calcium ATPases to disrupt calcium homeostasis and consequently induces ER stress. We have previously reported that TG induces apoptosis by engaging the death receptor 5 (DR5) and the intrinsic pathways. Second mitochondrial-derived activator (Smac) is an important modulator of apoptosis that induces activation of caspases by antagonizing inhibitors of apoptosis (IAPs). In this study, we have utilized Smac-proficient and -deficient human colon cancer cells to investigate the effects of Smac deficiency during ER-stress-induced apoptosis. Our results indicate that Smac deficiency considerably affects ER stress-induced apoptosis in human colon cancer cells. For example, ER stress inducing agent TG upregulates DR5, and activates caspases 3, 9 and 8 in Smac-proficient cells. In Smac-deficient cells, although TG-induced DR5 upregulation is not affected, activation of caspases 3, 9 and 8 is affected. Smac deficiency also affects TG-induced cytochrome c release from mitochondria into cytosol suggesting the existence of a potential cross-talk between Smac and cytochrome c. Thus, our results indicate that ER stress-induced apoptosis also engages Smac for transduction of apoptotic signals in human colon cancer cells and that a potential feedback signaling between Smac and cytochrome c appears to modulate the intrinsic pathway of apoptosis.