Laboratory of Cellular Metabolism and Metabolic Regulation, VIB-KU Leuven Center for Cancer Biology, VIB, Leuven, Belgium.
Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium.
Nature. 2019 Feb;566(7744):403-406. doi: 10.1038/s41586-019-0904-1. Epub 2019 Feb 6.
Most tumours have an aberrantly activated lipid metabolism that enables them to synthesize, elongate and desaturate fatty acids to support proliferation. However, only particular subsets of cancer cells are sensitive to approaches that target fatty acid metabolism and, in particular, fatty acid desaturation. This suggests that many cancer cells contain an unexplored plasticity in their fatty acid metabolism. Here we show that some cancer cells can exploit an alternative fatty acid desaturation pathway. We identify various cancer cell lines, mouse hepatocellular carcinomas, and primary human liver and lung carcinomas that desaturate palmitate to the unusual fatty acid sapienate to support membrane biosynthesis during proliferation. Accordingly, we found that sapienate biosynthesis enables cancer cells to bypass the known fatty acid desaturation pathway that is dependent on stearoyl-CoA desaturase. Thus, only by targeting both desaturation pathways is the in vitro and in vivo proliferation of cancer cells that synthesize sapienate impaired. Our discovery explains metabolic plasticity in fatty acid desaturation and constitutes an unexplored metabolic rewiring in cancers.
大多数肿瘤都存在异常激活的脂质代谢，使其能够合成、延长和去饱和脂肪酸以支持增殖。然而，只有特定的癌细胞亚群对靶向脂肪酸代谢的方法敏感，特别是脂肪酸去饱和。这表明许多癌细胞的脂肪酸代谢存在尚未被探索的可塑性。在这里，我们展示了一些癌细胞可以利用替代的脂肪酸去饱和途径。我们鉴定了各种癌细胞系、小鼠肝癌和原发性人肝和肺癌，它们将棕榈酸去饱和为不寻常的脂肪酸鲨烯酸，以在增殖过程中支持膜生物合成。因此，我们发现鲨烯酸生物合成使癌细胞能够绕过依赖硬脂酰辅酶 A 去饱和酶的已知脂肪酸去饱和途径。因此，只有靶向这两种去饱和途径，才能抑制合成鲨烯酸的癌细胞在体外和体内的增殖。我们的发现解释了脂肪酸去饱和的代谢可塑性，并构成了癌症中未被探索的代谢重排。
