The paradox of autophagy in Tuberous Sclerosis Complex

Abstract Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder caused by germline mutations in TSC1 or TSC2 genes, which leads to the hyperactivation of the mTORC1 pathway, an important negative regulator of autophagy. This leads to the development of hamartomas in multiple organs. The variability in symptoms presents a challenge for the development of completely effective treatments for TSC. One option is the treatment with mTORC1 inhibitors, which are targeted to block cell growth and restore autophagy. However, the therapeutic effect of rapamycin seems to be more efficient in the early stages of hamartoma development, an effect that seems to be associated with the paradoxical role of autophagy in tumor establishment. Under normal conditions, autophagy is directly inhibited by mTORC1. In situations of bioenergetics stress, mTORC1 releases the Ulk1 complex and initiates the autophagy process. In this way, autophagy promotes the survival of established tumors by supplying metabolic precursors during nutrient deprivation; paradoxically, excessive autophagy has been associated with cell death in some situations. In spite of its paradoxical role, autophagy is an alternative therapeutic strategy that could be explored in TSC. This review compiles the findings related to autophagy and the new therapeutic strategies targeting this pathway in TSC.

摘要 结节性硬化症（Tuberous sclerosis complex, TSC）是一种常染色体显性遗传病，由TSC1或TSC2基因的生殖系突变引发，可导致哺乳动物雷帕霉素靶蛋白复合物1（mTORC1）通路过度激活——该通路是自噬（autophagy）的重要负调控因子。该通路异常可引发多器官错构瘤的形成。临床症状的高度异质性为TSC的完全有效治疗带来了挑战。目前可选的治疗方案之一是使用mTORC1抑制剂，这类药物可靶向阻断细胞增殖并恢复自噬过程。然而，雷帕霉素（rapamycin）的治疗效果在错构瘤形成早期更为显著，这一现象似乎与自噬在肿瘤发生中的悖论性作用相关。在正常生理条件下，mTORC1会直接抑制自噬；而在生物能量应激状态下，mTORC1会释放Ulk1复合物（Ulk1 complex）并启动自噬过程。在此机制下，当营养匮乏时，自噬可通过提供代谢前体促进已形成肿瘤的存活；矛盾的是，在某些情境下过度激活的自噬又会引发细胞死亡。尽管自噬的作用存在悖论，但其仍是一种可供TSC治疗探索的新型策略。本综述汇总了与自噬相关的研究进展，以及靶向该通路用于TSC治疗的新型治疗策略。