Sestrins (SESN1-3) are a family of stress-responsive proteins that regulate cellular metabolism and redox balance, both of which are frequently disrupted in cancer. As direct targets of stress-responsive transcription factors, including tumour suppressor p53, Sestrins function as leucine-dependent inhibitors of mTORC1 and potent antioxidants. Their downregulation is widely observed across multiple cancers and is associated with increased tumour growth and poor prognosis. Despite their consistent tumour-suppressive effects through mTORC1 inhibition and promotion of p53-dependent apoptosis, Sestrins exhibit a limited role in tumour initiation, which appears to be context-dependent. Their antioxidant activity reduces oxidative damage, thereby protecting against genomic instability and other cancer-promoting events. However, in certain contexts, Sestrins may promote tumour survival and progression by stimulating pro-survival pathways, such as AKT signalling through mTORC2 activation. This review examines the molecular mechanisms underlying these dual functions, with a particular focus on mTOR signalling and oxidative stress. We also discuss Sestrin expression patterns and functional outcomes in various cancer types, including lung, liver, colon, skin, prostate, and follicular lymphomas, highlighting their potential as diagnostic markers and therapeutic targets.
Sestrins（SESN1-3）是一类应激反应蛋白家族，通过调控细胞代谢与氧化还原平衡在癌症发生发展中发挥重要作用。作为包括肿瘤抑制因子p53在内的应激反应转录因子的直接靶点，Sestrins既能作为亮氨酸依赖性mTORC1抑制剂，又具备强效抗氧化功能。在多种癌症中普遍观察到Sestrins表达下调，且与肿瘤生长加速及不良预后密切相关。尽管通过抑制mTORC1和促进p53依赖性凋亡持续发挥肿瘤抑制作用，但Sestrins在肿瘤起始阶段的作用有限且具有环境依赖性。其抗氧化活性可降低氧化损伤，从而防止基因组不稳定性等促癌事件。然而在某些特定环境下，Sestrins可能通过激活促生存通路（如经mTORC2激活AKT信号）促进肿瘤存活与进展。本综述重点探讨mTOR信号与氧化应激机制，解析Sestrins双重功能的分子基础，并系统阐述其在肺癌、肝癌、结肠癌、皮肤癌、前列腺癌及滤泡性淋巴瘤等多种癌症中的表达模式与功能效应，揭示其作为诊断标志物和治疗靶点的潜在价值。
Sestrins in Carcinogenesis—The Firefighters That Sometimes Stoke the Fire
肿瘤(癌症)患者之家