肿瘤细胞内质网应激保护:热休克蛋白TRAP1的多方面作用

IF 0.7
Danilo Swann Matassa, Diana Arzeni, M. Landriscina, F. Esposito
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引用次数: 3

摘要

TRAP1是一种HSP90伴侣蛋白,在人类癌症中表达上调,参与细胞器稳态和肿瘤细胞代谢。事实上,TRAP1是高增殖肿瘤面对蛋白质合成需求增加和恶劣环境引起的代谢应激时所使用的适应性反应的关键调节因子。除了在防止线粒体通透性过渡开孔和调节线粒体呼吸方面具有众所周知的作用外,TRAP1还参与了新的调节机制:1)全球蛋白质合成的减弱,2)蛋白质合成和特定客户蛋白泛素化的共翻译调节,以及3)内质网应激的保护。这为TRAP1通过蛋白质质量控制维持细胞稳态提供了关键作用,避免了受损或错误折叠蛋白质的积累,并可能促进了选择性癌症相关蛋白质的合成。在此,我们总结了这些调节机制如何成为一个综合网络的一部分,该网络使癌细胞能够调节其代谢,同时面临氧化和代谢应激,氧气和营养剥夺,能量生产和大分子生物合成需求增加。采取一种新的策略来破坏癌细胞中这种综合控制网络的可能性,为治疗人类恶性肿瘤带来了巨大的希望。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
ER stress protection in cancer cells: the multifaceted role of the heat shock protein TRAP1
Abstract TRAP1 is an HSP90 chaperone, upregulated in human cancers and involved in organelles’ homeostasis and tumor cell metabolism. Indeed, TRAP1 is a key regulator of adaptive responses used by highly proliferative tumors to face the metabolic stress induced by increased demand of protein synthesis and hostile environments. Besides well-characterized roles in prevention of mitochondrial permeability transition pore opening and in regulating mitochondrial respiration, TRAP1 is involved in novel regulatory mechanisms: i) the attenuation of global protein synthesis, ii) the co-translational regulation of protein synthesis and ubiquitination of specific client proteins, and iii) the protection from Endoplasmic Reticulum stress. This provides a crucial role to TRAP1 in maintaining cellular homeostasis through protein quality control, by avoiding the accumulation of damaged or misfolded proteins and, likely, facilitating the synthesis of selective cancer-related proteins. Herein, we summarize how these regulatory mechanisms are part of an integrated network, which enables cancer cells to modulate their metabolism and to face, at the same time, oxidative and metabolic stress, oxygen and nutrient deprivation, increased demand of energy production and macromolecule biosynthesis. The possibility to undertake a new strategy to disrupt such networks of integrated control in cancer cells holds great promise for treatment of human malignancies.
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