Stressed to death: targeting endoplasmic reticulum stress response induced apoptosis in gliomas.
Stressed to death: targeting endoplasmic reticulum stress response induced apoptosis in gliomas.
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DOI：
10.2174/138161211795049660
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发表时间：
2011
影响因子：
3.1
通讯作者：
Grimaldi M
中科院分区：
文献类型：
--
作者：
Johnson GG;White MC;Grimaldi M
胶质瘤是成人主要的原发脑肿瘤。即使采用最先进的治疗方法，包括立体定向显微镜辅助手术切除、内外放射治疗以及局部和全身化疗，被诊断为这些恶性肿瘤的患者的中位生存期约为12个月。我们在这里探索内质网应激反应(ERSR)可能成为开发化疗药物以诱导胶质瘤细胞毒性的可能靶点。ERSR具有激活修复和/或细胞毒机制的双重功能。ERSR是由内质网中未折叠蛋白的积累触发的。内质网中未折叠蛋白的存在通过复杂的生物化学级联调控分子伴侣的上调、蛋白质合成的抑制和蛋白酶体介导的未折叠蛋白降解的增加。在特定条件下，ERSR也可以通过激活程序性细胞死亡来促进细胞死亡。ERSR过程中的细胞凋亡激活通常是由三个生化级联中的一个或三个生化级联的组合激活引起的。这些途径的诱导最终导致caspase3的激活，最终导致细胞凋亡。胶质瘤细胞处于持续的低级别ERSR状态，这可能是导致其对治疗方案产生抵抗的原因之一。可以想象，与这一现象相互作用的小分子最终可能被用来调节系统，以激活细胞凋亡并导致神经胶质毒性。我们将在这里讨论ERSR与死亡机制的生化相关特征，以及已经确定的通过调节ERSR能够激活胶质瘤细胞死亡的小分子。
Glial tumors are the main primary adult brain tumor. Even with the most advanced treatments, which include stereotactic microscope aided surgical resection, internal and external radiation therapy and local and systemic chemotherapy, median survival time for patients diagnosed with these malignancies is about 12 months. We explore here the possibility that the endoplasmic reticulum stress response (ERSR) could be a possible target to develop chemotherapeutic agents to induce toxicity in glioma cells. ERSR has the dual capacity of activating repair and/or cytotoxic mechanisms. ERSR is triggered by the accumulation of unfolded proteins in the ER. The presence of unfolded proteins in the ER regulates, via a complex biochemical cascade, the upregulation of molecular chaperones, inhibition of protein synthesis, and an increase of proteasome mediated unfolded protein degradation. ERSR in particular conditions can also contribute to cell death via activation of programmed cell death. Apoptosis activation during ERSR is usually caused by the activation of one or a combination of three biochemical cascades. Induction of these pathways ultimately leads to caspase 3 activation culminating in apoptosis. Glioma cells are in a condition of constant low grade ERSR, which possibly contributes to their resistance to treatment protocols. It is conceivable that small molecules that interact with this phenomenon ultimately could be used to modulate the system to activate apoptosis and cause gliotoxicity. We will discuss here ERSR biochemically relevant features to death mechanisms and already identified small molecules that by modulating ERSR are able to activate glioma cell death.