热休克蛋白家族调控代谢网络促进肿瘤恶性进展的新范式

A New Paradigm for the Regulation of Metabolic Networks by Heat Shock Protein Family in Promoting Malignant Tumor Progression

摘要

代谢重编程是癌症的重要特征之一，其调控机制不仅依赖于代谢酶活性的改变，更涉及广泛的蛋白-蛋白相互作用网络。热休克蛋白（heat shock protein, HSP）家族是细胞内重要的分子伴侣系统，广泛参与肿瘤代谢重编程的调控。系统梳理 HSP 驱动肿瘤代谢重编程与恶性进展的最新研究进展，提出“HSP-代谢轴”整合调控框架：1）直接结合并稳定糖酵解、三羧酸循环、脂质代谢等通路的关键代谢酶；2）调控哺乳动物雷帕霉素靶蛋白、缺氧诱导因子-1α 等信号分子，系统重塑肿瘤代谢状态；3）作为支架蛋白组装代谢酶-信号蛋白复合体，在时空维度实现代谢过程与信号转导的耦合联动。在此基础上对比分析了不同 HSP 成员的代谢调控特征及代表性抑制剂的研究现状。相关研究阐明了 HSP 调控肿瘤代谢网络的全新功能，为开发靶向 HSP 的抗肿瘤干预策略提供了理论依据。

Abstract

Metabolic reprogramming represents one of the core hallmarks of cancer, and the underlying regulatory mechanisms are attributable not only to alterations in the activities of metabolic enzymes, but also to the participation of elaborate protein-protein interaction networks. As a key intracellular molecular chaperone system, the heat shock protein (HSP) family is extensively involved in the regulation of tumor metabolic reprogramming. This review systematically summarizes the latest research progress of HSP-driven tumor metabolic reprogramming and malignant tumor progression, and proposes an integrated regulatory framework termed the “HSP-metabolism axis”: 1) directly binding to and stabilizing key metabolic enzymes involved in glycolysis, tricarboxylic acid cycle, lipid metabolism and other metabolic pathways; 2) regulating signaling molecules such as mammalian target of rapamycin and hypoxia-inducible factor-1α, to systematically reshape tumor metabolic profiles; and 3) assembling metabolic enzyme-signaling protein complexes as scaffold proteins, thereby coupling metabolic processes and signal transduction in a spatiotemporal manner. On this basis, this paper compares the metabolic regulatory features of distinct HSP members and reviews the research status of their representative HSP inhibitors. Relevant studies have clarified the novel function of HSPs in modulating tumor metabolic networks, providing a theoretical basis for the development of anti-tumor strategies targeting HSPs.

关键词

热休克蛋白 / 分子伴侣 / 代谢重编程 / 蛋白-蛋白相互作用 / 代谢酶 / 肿瘤恶性进展

Key words

heat shock protein / molecular chaperone / metabolic reprogramming / protein-protein interaction / metabolic enzyme / malignant tumor progression

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基金资助

国家自然科学基金面上项目(82473936)