Wlodkowic Donald, Skommer Joanna, McGuinness Dagmara, Hillier Chris, Darzynkiewicz Zbigniew
Department of Biological & Biomedical Sciences, Glasgow Caledonian University, Glasgow, UK.
Leuk Res. 2009 Nov;33(11):1440-7. doi: 10.1016/j.leukres.2009.05.025.
Tumor cell demise is an important event in the elimination of abnormal malignant cells and provides an important mechanism of natural tumor suppression. Abnormalities incapacitating these finely tuned processes provide a strong advantage for cancer clones to succeed in evading both the physiological control systems and therapeutic intervention. Expanding our knowledge of the molecular "crosstalks" that regulate tumor cell demise is crucial in guiding the successful design of future anti-cancer therapeutics. Although currently available data indicate that elimination of malignant cells often depends on classical apoptotic pathways (mitochondrial and/or death-receptor pathways), the evidence is mounting that alternative apoptotic and non-apoptotic pathways may effectively contribute to tumor cell death. The assumption that every organelle is capable of sensing, amplificating and executing cell death is also a relatively novel and unexplored concept. As recently shown, the secretory pathway can be actively involved in sensing stress stimuli and possibly even initiating and propagating cell death signaling. Experimental evidence indicates that ER and Golgi apparatus can activate both pro-survival (recovery) mechanisms as well as cell suicide programs if the stress-signaling threshold is exceeded. It is thus conceivable that the fragile balance of protein trafficking between various subcellular compartments provides an exceptional therapeutic opportunity. Interestingly, a growing number of reports recognize novel therapeutic targets, including proteins in control of endoplasmic reticulum (ER) and Golgi homeostasis. Further studies are, however, needed to elucidate precise signaling pathways emanating from ER-Golgi compartment. Development of more potent and selective small-molecule drugs that activate ER-Golgi mediated cell demise is also needed. As the interest in the role of ER-Golgi network during cancer cell death has been gaining momentum, we attempt here to critically appraise current status of development of investigational anti-cancer agents that target ER and/or Golgi.
肿瘤细胞死亡是消除异常恶性细胞的重要事件，也是自然肿瘤抑制的重要机制。使这些精细调节过程失效的异常情况为癌症克隆成功逃避生理控制系统和治疗干预提供了强大优势。扩展我们对调节肿瘤细胞死亡的分子“串扰”的认识，对于指导未来抗癌治疗的成功设计至关重要。尽管目前可得的数据表明，恶性细胞的消除通常依赖于经典的凋亡途径（线粒体和/或死亡受体途径），但越来越多的证据表明，替代性凋亡和非凋亡途径可能有效地导致肿瘤细胞死亡。每个细胞器都能够感知、放大并执行细胞死亡的假设也是一个相对新颖且未被探索的概念。最近的研究表明，分泌途径可积极参与应激刺激的感知，甚至可能启动和传播细胞死亡信号。实验证据表明，如果应激信号阈值被超过，内质网（ER）和高尔基体可激活促生存（恢复）机制以及细胞自杀程序。因此可以想象，各种亚细胞区室之间蛋白质运输的脆弱平衡提供了一个特殊的治疗机会。有趣的是，越来越多的报告认识到了新的治疗靶点，包括控制内质网（ER）和高尔基体稳态的蛋白质。然而，需要进一步研究来阐明源自内质网-高尔基体区室的精确信号通路。还需要开发更有效和选择性的小分子药物，以激活内质网-高尔基体介导的细胞死亡。随着对内质网-高尔基体网络在癌细胞死亡过程中作用的兴趣日益浓厚，我们在此试图批判性地评估针对内质网和/或高尔基体的研究性抗癌药物的开发现状。
