蛋白质稳态的抗肿瘤策略及其临床意义

Anti-cancer strategies from the perspective of protein homeostasis and their clinical implications

蛋白质构象易受到细胞蛋白质组压力的影响,如致病性突变、环境压力。蛋白质稳态通过调节蛋白质的合成、折叠、翻译后的修饰和细胞环境中的降解,维持蛋白质功能折叠的微妙平衡。蛋白质稳态的失衡会导致错误折叠的蛋白质的聚集和积累,构成蛋白质构象疾病,包括某些类型的恶性肿瘤、神经退行性疾病。肿瘤细胞高度依赖蛋白质稳态,功能失调的细胞恶性增殖和转移往往需要快速的蛋白质合成和足够的下游质量控制能力。肿瘤细胞内超负荷合成超过了蛋白质平衡网络的能力,导致蛋白质构象上的缺陷。因此,干预蛋白质稳态已被证明是一种有前景的抗肿瘤治疗策略,现就蛋白质稳态角度讨论抗肿瘤治疗及其临床意义并进行综述。

Protein conformation is susceptible to cellular proteomic stresses,such as pathogenic mutations and environmental stresses.Protein homeostasis maintains a delicate balance of the functional folding of proteins in response to these stresses by regulating protein synthesis,folding,post-translational modification and intracelluar degradation.Imbalances in protein homeostasis lead to the aggregation and accumulation of misfolded proteins,which constitute hallmark events of protein conformational diseases,including certain types of cancers and neurodegenerative diseases.Tumor cells are highly dependent on protein homeostasis,and dysfunctional cancer proliferation and metastasis often require rapid protein synthesis and adequate downstream quality control capabilities.Overloaded synthesis in tumor cells exceeds the capacity of the protein homeostasis network,leading to defects in protein conformation.Intervening in protein homeostasis has thus been shown to be a promising therapeutic strategy against cancer.This paper reviews anti-tumor strategies from the perspective of protein homeostasis and discusses their clinical implications.