Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Autophagy. 2011 Nov;7(11):1400-1. doi: 10.4161/auto.7.11.17652. Epub 2011 Nov 1.
Mammalian target of rapamycin (mTOR) complex 1 (mTORC1), which is activated in tuberous sclerosis complex (TSC) and lymphangioleiomyomatosis (LAM), is a master regulator of cell growth, cellular metabolism, and autophagy. Treatment of TSC and LAM patients with mTORC1 inhibitors partially decreases the size of brain and kidney tumors, and stabilizes pulmonary function. However, the tumors regrow and lung function continues to decline when treatment is discontinued. We hypothesized that dysregulation of autophagy plays a critical role in the pathogenesis of tumors with mTORC1 hyperactivation and in their response to mTORC1-targeted therapy. We found that cells lacking TSC2 have low levels of autophagy under basal and cellular stress conditions. Using genetic and pharmacological approaches, we discovered that the survival of Tsc2-deficient tumor cells is dependent on autophagy induction. Thus, autophagy inhibitors may have therapeutic potential in TSC and LAM, either as single agent therapy or in combination with mTORC1 inhibitors.
哺乳动物雷帕霉素靶蛋白（mTOR）复合物 1（mTORC1）在结节性硬化症（TSC）和淋巴管平滑肌瘤病（LAM）中被激活，是细胞生长、细胞代谢和自噬的主要调节剂。用 mTORC1 抑制剂治疗 TSC 和 LAM 患者可部分减小脑和肾肿瘤的大小，并稳定肺功能。然而，当治疗停止时，肿瘤会重新生长，肺功能继续下降。我们假设自噬失调在 mTORC1 过度激活的肿瘤的发病机制及其对 mTORC1 靶向治疗的反应中起着关键作用。我们发现，在基础和细胞应激条件下，缺乏 TSC2 的细胞自噬水平较低。通过遗传和药理学方法，我们发现 Tsc2 缺陷肿瘤细胞的存活依赖于自噬的诱导。因此，自噬抑制剂可能具有治疗 TSC 和 LAM 的潜力，无论是作为单一药物治疗还是与 mTORC1 抑制剂联合使用。
