Protein homeostasis or proteostasis, the correct balance between production and degradation of proteins, is an essential pillar for proper cellular function. Among the several cellular mechanisms that disrupt homeostatic conditions in cancer cells, hyperthermia (HT) has shown promising anti-tumor effects. However, cancer cells are also capable of thermoresistance. Indeed, HT-induced protein denaturation and aggregation results in the up regulation of heat shock proteins, a group of molecular chaperones with cytoprotective and anti-apoptotic properties via stress-inducible transcription factor, heat shock factor 1(HSF1). Heat shock proteins assist in the refolding of misfolded proteins and aids in their elimination if they become irreversibly damaged by various stressors. Furthermore, HSF1 also initiates the unfolded protein response in the endoplasmic reticulum (ER) to assist in the protein folding capacity of ER and also promotes the translation of pro-survival proteins' mRNA such as activating transcription factor 4 (ATF 4). Moreover, HT associated induction of microRNAs is also involved in thermal resistance of cancer cells via up-regulation of anti-apoptotic Bcl-2 proteins and down regulation of pro-apoptotic Bax and caspase 3 activities. Another cellular protection in response to stressors is Autophagy, which is regulated by the Mammalian target of rapamycin (mTOR) protein. Kinase activity in mTOR phosphorylates HSF1 and promotes its nuclear translocation for heat shock protein synthesis. Over-expression of heat shock proteins are reported to up-regulate Beclin-1, an autophagy initiator. Moreover, HT-induced reactive oxygen species (ROS) generation is sensitized by transcription factor NF-E2 related factor 2 (Nrf2) and activates the cellular expression of antioxidants and autophagy gene. Furthermore, ROS also potentiates autophagy via activation of Beclin-1. Inhibition of thermotolerance can potentiate HT-induced apoptosis. Here, we outlined that heat stress alters cellular proteins which activates cellular homeostatic processes to promote cell survival and make cancer cells thermotolerant.

中文翻译：

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热疗和蛋白质稳态：细胞保护和细胞死亡

蛋白质稳态或蛋白质稳态，即蛋白质产生和降解之间的正确平衡，是正常细胞功能的重要支柱。在破坏癌细胞稳态条件的几种细胞机制中，热疗 (HT) 已显示出有希望的抗肿瘤作用。然而，癌细胞也具有耐热性。事实上，HT 诱导的蛋白质变性和聚集导致热休克蛋白的上调，这是一组通过应激诱导转录因子热休克因子 1 (HSF1) 具有细胞保护和抗凋亡特性的分子伴侣。热休克蛋白有助于错误折叠蛋白的重新折叠，并在它们被各种压力源不可逆转地损坏时帮助消除它们。此外，HSF1 还启动内质网 (ER) 中未折叠的蛋白质反应，以协助 ER 的蛋白质折叠能力，并促进促存活蛋白 mRNA 的翻译，例如激活转录因子 4 (ATF 4)。此外，通过上调抗凋亡 Bcl-2 蛋白和下调促凋亡 Bax 和半胱天冬酶 3 活性，HT 相关 microRNA 的诱导也参与了癌细胞的耐热性。另一种应对压力源的细胞保护是自噬，它受哺乳动物雷帕霉素靶蛋白 (mTOR) 蛋白的调节。mTOR 中的激酶活性使 HSF1 磷酸化并促进其核转位以合成热休克蛋白。据报道，热休克蛋白的过度表达会上调 Beclin-1，一种自噬引发剂。而且，HT 诱导的活性氧 (ROS) 生成被转录因子 NF-E2 相关因子 2 (Nrf2) 敏化，并激活抗氧化剂和自噬基因的细胞表达。此外，ROS 还通过激活 Beclin-1 增强自噬。抑制耐热性可以增强 HT 诱导的细胞凋亡。在这里，我们概述了热应激会改变细胞蛋白质，这些蛋白质会激活细胞稳态过程以促进细胞存活并使癌细胞具有耐热性。