Acidosis Drives the Reprogramming of Fatty Acid Metabolism in Cancer Cells through Changes in Mitochondrial and Histone Acetylation
Acidosis Drives the Reprogramming of Fatty Acid Metabolism in Cancer Cells through Changes in Mitochondrial and Histone Acetylation
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DOI：
10.1016/j.cmet.2016.07.003
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发表时间：
2016-08-09
期刊：
影响因子：
29
通讯作者：
Feron, Olivier
中科院分区：
文献类型：
--
作者：
Corbet, Cyril;Pinto, Adan;Feron, Olivier
癌细胞的生物能量偏好促进肿瘤酸中毒，这反过来导致糖酵解和葡萄糖衍生的乙酰辅酶A（乙酰辅酶A）的急剧减少。在这里，我们表明，这种关键的两碳中间体的主要来源成为脂肪酸（FA）氧化酸性pH适应癌细胞。FA衍生的乙酰辅酶A不仅为三羧酸（TCA）循环提供燃料并支持酸中毒下的肿瘤细胞呼吸，而且还有助于非酶促线粒体蛋白的超乙酰化，从而抑制复合物I活性和ROS产生。此外，虽然谷氨酰胺的氧化代谢支持在酸性条件下的典型TCA循环，但谷氨酰胺衍生的α-酮戊二酸的还原羧化维持FA合成。伴随的FA氧化和合成是在沉默调节蛋白介导的组蛋白脱乙酰化和乙酰辅酶A羧化酶ACC 2的连续下调后实现的，使得线粒体脂肪酰辅酶A降解与细胞溶质脂肪生成相容。这些调节过程的扰动导致肿瘤生长抑制作用，进一步确定FA代谢是酸中毒下肿瘤细胞增殖的关键决定因素。
Bioenergetic preferences of cancer cells foster tumor acidosis that in turn leads to dramatic reduction in glycolysis and glucose-derived acetyl-coenzyme A (acetyl-CoA). Here, we show that the main source of this critical two-carbon intermediate becomes fatty acid (FA) oxidation in acidic pH-adapted cancer cells. FA-derived acetyl-CoA not only fuels the tricarboxylic acid (TCA) cycle and supports tumor cell respiration under acidosis, but also contributes to non-enzymatic mitochondrial protein hyperacetylation, thereby restraining complex I activity and ROS production. Also, while oxidative metabolism of glutamine supports the canonical TCA cycle in acidic conditions, reductive carboxylation of glutamine-derived alpha-ketoglutarate sustains FA synthesis. Concomitance of FA oxidation and synthesis is enabled upon sirtuin-mediated histone deacetylation and consecutive downregulation of acetyl-CoA carboxylase ACC2 making mitochondrial fatty acyl-CoA degradation compatible with cytosolic lipogenesis. Perturbations of these regulatory processes lead to tumor growth inhibitory effects further identifying FA metabolism as a critical determinant of tumor cell proliferation under acidosis.