Hypoxic and Ras-transformed cells support growth by scavenging unsaturated fatty acids from lysophospholipids
Hypoxic and Ras-transformed cells support growth by scavenging unsaturated fatty acids from lysophospholipids
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DOI：
10.1073/pnas.1307237110
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发表时间：
2013-05-28
影响因子：
11.1
通讯作者：
Rabinowitz, Joshua D.
中科院分区：
文献类型：
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作者：
Kamphorst, Jurre J.;Cross, Justin R.;Rabinowitz, Joshua D.
癌细胞的生长需要脂肪酸来复制细胞膜。已知Akt激酶上调脂肪酸合成和去饱和，这是由耗氧酶硬脂酰辅酶a去饱和酶（SCD）1完成的。我们使用C-13示踪剂和脂质组学来探测脂肪酸代谢，包括去饱和，作为癌基因表达和氧可用性的功能。在缺氧时，葡萄糖到乙酰辅酶a的通量减少，谷氨酰胺对脂肪酸合成的部分贡献增加。此外，我们发现缺氧细胞通过清除血清脂肪酸，绕过了重新生成脂肪，从而既需要乙酰辅酶a，也需要氧依赖性scd1反应。清除的首选底物是具有一个脂肪酸尾部的磷脂（溶血磷脂）。低氧重编程的新生脂肪生成可以通过Ras激活在常氧细胞中复制。这使得ras驱动的细胞，无论是在培养中还是在同种异体移植物中，都能抵抗SCD1的抑制。因此，致癌Ras赋予代谢稳健性的机制是通过脂质清除。
Cancer cell growth requires fatty acids to replicate cellular membranes. The kinase Akt is known to up-regulate fatty acid synthesis and desaturation, which is carried out by the oxygen-consuming enzyme stearoyl-CoA desaturase (SCD)1. We used C-13 tracers and lipidomics to probe fatty acid metabolism, including desaturation, as a function of oncogene expression and oxygen availability. During hypoxia, flux from glucose to acetyl-CoA decreases, and the fractional contribution of glutamine to fatty acid synthesis increases. In addition, we find that hypoxic cells bypass de novo lipogenesis, and thus, both the need for acetyl-CoA and the oxygen-dependent SCD1-reaction, by scavenging serum fatty acids. The preferred substrates for scavenging are phospholipids with one fatty acid tail (lysophospholipids). Hypoxic reprogramming of de novo lipogenesis can be reproduced in normoxic cells by Ras activation. This renders Ras-driven cells, both in culture and in allografts, resistant to SCD1 inhibition. Thus, a mechanism by which oncogenic Ras confers metabolic robustness is through lipid scavenging.