Targeting β-tubulin:CCT-β complexes incurs Hsp90- and VCP-related protein degradation and induces ER stress-associated apoptosis by triggering capacitative Ca2+ entry, mitochondrial perturbation and caspase overactivation.
Targeting β-tubulin:CCT-β complexes incurs Hsp90- and VCP-related protein degradation and induces ER stress-associated apoptosis by triggering capacitative Ca2+ entry, mitochondrial perturbation and caspase overactivation.
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DOI：
10.1038/cddis.2012.173
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发表时间：
2012-11-29
影响因子：
9
通讯作者：
Liang, P-H
中科院分区：
文献类型：
--
作者：
Lin, Y-F;Lee, Y-F;Liang, P-H
我们之前已经证明，阻断β-微管蛋白的蛋白-蛋白相互作用（PPI）：含有伴侣蛋白的TCP-1β (CCT-β)可诱导由于CCT-β过表达而选择性杀死多药耐药癌细胞。然而，分子机制尚未确定。在这项研究中，我们发现CCT-β与无数细胞内蛋白相互作用，参与内质网（ER）、线粒体、细胞骨架、蛋白酶体和凋亡体的细胞功能。我们的数据表明，靶细胞激活热休克蛋白90 （Hsp90）相关蛋白泛素化/降解途径，以消除细胞质中错误折叠的蛋白质，以及以含缬氨酸蛋白（VCP）为中心的内质网相关蛋白降解途径，以减少内质网过多的未折叠多肽水平，从而减轻内质网应激，在β-微管蛋白：CCT-β复合物破坏开始时。一旦内质网应激扩大，内质网应激相关的凋亡信号被强制执行，表现为细胞空泡化和细胞内Ca2+释放。此外，细胞内Ca2+水平升高引起的Ca2+进入引起线粒体扰动和靶细胞的半胱天冬酶过度激活，从而增强凋亡信号。这些发现不仅提供了靶向β-微管蛋白：CCT-β复合物引起的凋亡信号级联的详细图像，而且还展示了一种对抗恶性肿瘤的策略，该策略具有对Hsp90和vcp相关抗癌药物的化学耐药。
We have previously demonstrated that interrupting the protein–protein interaction (PPI) of β-tubulin:chaperonin-containing TCP-1β (CCT-β) induces the selective killing of multidrug-resistant cancer cells due to CCT-β overexpression. However, the molecular mechanism has not yet been identified. In this study, we found that CCT-β interacts with a myriad of intracellular proteins involved in the cellular functions of the endoplasmic reticulum (ER), mitochondria, cytoskeleton, proteasome and apoptosome. Our data show that the targeted cells activate both the heat-shock protein 90 (Hsp90)-associated protein ubiquitination/degradation pathway to eliminate misfolded proteins in the cytoplasm and the valosin-containing protein (VCP)-centered ER-associated protein degradation pathway to reduce the excessive levels of unfolded polypeptides from the ER, thereby mitigating ER stress, at the onset of β-tubulin:CCT-β complex disruption. Once ER stress is expanded, ER stress-associated apoptotic signaling is enforced, as exhibited by cellular vacuolization and intracellular Ca2+ release. Furthermore, the elevated intracellular Ca2+ levels resulting from capacitative Ca2+ entry augments apoptotic signaling by provoking mitochondrial perturbation and caspase overactivation in the targeted cells. These findings not only provide a detailed picture of the apoptotic signaling cascades evoked by targeting the β-tubulin:CCT-β complex but also demonstrate a strategy to combat malignancies with chemoresistance to Hsp90- and VCP-related anticancer agents.
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