Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA; Hunan University of Chinese Medicine, Changsha, China.
Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA; Department of Neurosciences, Cleveland Clinic, Cleveland, Ohio, USA.
J Invest Dermatol. 2021 Sep;141(9):2291-2299.e2. doi: 10.1016/j.jid.2021.02.754. Epub 2021 Mar 26.
Tuberous sclerosis complex (TSC) is an autosomal-dominant disorder characterized by hamartomatous tumors of the skin, kidneys, brain, and lungs. TSC is caused by mutations in the TSC1 and TSC2 genes, which result in hyperactivation of the mTOR, leading to dysregulated cell growth and autophagy. Rapamycin (sirolimus) shrinks TSC tumors, but the clinical benefits of sirolimus are not sustained after its withdrawal. In this study, we studied the cellular processes critical for tumor formation and growth, including cell proliferation and cell size. TSC2 and TSC2 cells were isolated from TSC skin tumors and normal-appearing skin, respectively. Cells were incubated with sirolimus for 72 hours. Withdrawal of sirolimus from TSC2 cells resulted in a highly proliferative phenotype and caused cells to enter the S phase of the cell cycle, with persistent phosphorylation of mTOR, p70 S6 kinase, ribosomal protein S6, and 4EB-P1; decreased cyclin D kinase inhibitors; and transient hyperactivation of protein kinase B. Sirolimus modulated the estrogen- and autophagy-dependent volume of TSC2 cells. These results suggest that sirolimus may decrease the size of TSC tumors by reducing TSC2 cell volume, altering the cell cycle, and reprogramming TSC2-null cells.
结节性硬化症复合征（TSC）是一种常染色体显性遗传病，其特征为皮肤、肾脏、大脑和肺部的错构瘤。TSC 是由 TSC1 和 TSC2 基因突变引起的，导致 mTOR 的过度激活，从而导致细胞生长和自噬的失调。雷帕霉素（西罗莫司）可使 TSC 肿瘤缩小，但在停药后，西罗莫司的临床获益不能持续。在这项研究中，我们研究了对肿瘤形成和生长至关重要的细胞过程，包括细胞增殖和细胞大小。我们分别从 TSC 皮肤肿瘤和正常外观的皮肤中分离出 TSC2 和 TSC2 细胞。将细胞用西罗莫司孵育 72 小时。从 TSC2 细胞中撤去西罗莫司导致高度增殖表型，并使细胞进入细胞周期的 S 期，mTOR、p70 S6 激酶、核糖体蛋白 S6 和 4EB-P1 持续磷酸化；细胞周期蛋白 D 激酶抑制剂减少；蛋白激酶 B 短暂过度激活。西罗莫司调节 TSC2 细胞的雌激素和自噬依赖性体积。这些结果表明，西罗莫司可能通过减少 TSC2 细胞体积、改变细胞周期和重编程 TSC2 缺失细胞来减小 TSC 肿瘤的大小。
