Laboratory of Cellular Metabolism and Metabolic Regulation, VIB-KU Leuven Center for Cancer Biology, VIB, Herestraat 49, 3000 Leuven, Belgium; Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Herestraat 49, 3000 Leuven, Belgium.
Division of Tumor Metabolism and Microenvironment, German Cancer Research Center, Im Neuenheimer Feld 581, 69120 Heidelberg, Germany; Faculty of Biosciences, University of Heidelberg, 69120 Heidelberg, Germany.
Cell Rep. 2020 Jun 23;31(12):107806. doi: 10.1016/j.celrep.2020.107806.
Cancer cells display an increased plasticity in their lipid metabolism, which includes the conversion of palmitate to sapienate via the enzyme fatty acid desaturase 2 (FADS2). We find that FADS2 expression correlates with mammalian target of rapamycin (mTOR) signaling and sterol regulatory element-binding protein 1 (SREBP-1) activity across multiple cancer types and is prognostic in some cancer types. Accordingly, activating mTOR signaling by deleting tuberous sclerosis complex 2 (Tsc2) or overexpression of SREBP-1/2 is sufficient to increase FADS2 mRNA expression and sapienate metabolism in mouse embryonic fibroblasts (MEFs) and U87 glioblastoma cells, respectively. Conversely, inhibiting mTOR signaling decreases FADS2 expression and sapienate biosynthesis in MEFs with Tsc2 deletion, HUH7 hepatocellular carcinoma cells, and orthotopic HUH7 liver xenografts. In conclusion, we show that mTOR signaling and SREBP activity are sufficient to activate sapienate metabolism by increasing FADS2 expression. Consequently, targeting mTOR signaling can reduce sapienate metabolism in vivo.
癌细胞的脂代谢具有较高的可塑性，包括通过脂肪酸去饱和酶 2（FADS2）将棕榈酸转化为鲨烯酸。我们发现，FADS2 的表达与多种癌症类型的雷帕霉素靶蛋白（mTOR）信号和固醇调节元件结合蛋白 1（SREBP-1）活性相关，并且在某些癌症类型中具有预后价值。因此，通过删除结节性硬化复合物 2（Tsc2）或过表达 SREBP-1/2 来激活 mTOR 信号足以分别增加小鼠胚胎成纤维细胞（MEFs）和 U87 神经胶质瘤细胞中的 FADS2 mRNA 表达和鲨烯酸代谢。相反，在 Tsc2 缺失的 MEFs、HUH7 肝癌细胞和原位 HUH7 肝异种移植瘤中，抑制 mTOR 信号会降低 FADS2 的表达和鲨烯酸的生物合成。总之，我们表明 mTOR 信号和 SREBP 活性足以通过增加 FADS2 的表达来激活鲨烯酸代谢。因此，靶向 mTOR 信号可以减少体内的鲨烯酸代谢。
