Heat Shock Proteins and HSF1 in Cancer.
Heat Shock Proteins and HSF1 in Cancer.
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DOI：
10.3389/fonc.2022.860320
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发表时间：
2022
影响因子：
4.7
通讯作者：
Zhitkovich A
中科院分区：
文献类型：
--
作者：
Cyran AM;Zhitkovich A
细胞的适应性依赖于蛋白质稳态，而蛋白质稳态是通过蛋白质伴侣和蛋白质水解机制的协同活动来维持的。在遇到蛋白质损伤条件时，细胞激活热休克反应（HSR），其中涉及hsf1介导的一组伴侣蛋白-热休克蛋白（HSPs）的转录上调。由于突变蛋白的产生、非整倍体诱导的多蛋白复合物组分过量、翻译率增加和代谢失调，癌细胞经历了高水平的蛋白质毒性应激。为了应对这种慢性的蛋白毒性应激状态，癌症几乎总是上调HSR的主要成分，包括HSF1和单个hsp。一些致癌程序显示与特定HSR因子（如HSF1和MYC基因的频繁共扩增）的依赖性或偶联性。HSPs和HSF1水平升高通常与各种恶性肿瘤的耐药性和不良临床结果相关。对蛋白质质量控制的非癌基因依赖（“成瘾”）代表了治疗人类恶性肿瘤的胰腺癌靶点，提供了提高标准和靶向化疗和免疫检查点抑制剂疗效的潜力。在具有特定依赖性的癌症中，HSR成分可以作为可药物性差的致癌驱动因素的替代靶点。
Fitness of cells is dependent on protein homeostasis which is maintained by cooperative activities of protein chaperones and proteolytic machinery. Upon encountering protein-damaging conditions, cells activate the heat-shock response (HSR) which involves HSF1-mediated transcriptional upregulation of a group of chaperones – the heat shock proteins (HSPs). Cancer cells experience high levels of proteotoxic stress due to the production of mutated proteins, aneuploidy-induced excess of components of multiprotein complexes, increased translation rates, and dysregulated metabolism. To cope with this chronic state of proteotoxic stress, cancers almost invariably upregulate major components of HSR, including HSF1 and individual HSPs. Some oncogenic programs show dependence or coupling with a particular HSR factor (such as frequent coamplification of HSF1 and MYC genes). Elevated levels of HSPs and HSF1 are typically associated with drug resistance and poor clinical outcomes in various malignancies. The non-oncogene dependence (“addiction”) on protein quality controls represents a pancancer target in treating human malignancies, offering a potential to enhance efficacy of standard and targeted chemotherapy and immune checkpoint inhibitors. In cancers with specific dependencies, HSR components can serve as alternative targets to poorly druggable oncogenic drivers.
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影响因子：
1.6
作者：
Ağababaoğlu İ;Önen A;Demir AB;Aktaş S;Altun Z;Ersöz H;Şanl A;Özdemir N;Akkoçlu A
通讯作者：
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作者：
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作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
3.4
作者：
Brocchieri L;Conway de Macario E;Macario AJ
通讯作者：
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