Department of Molecular and Cellular Endocrinology, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
Department of Molecular and Cellular Endocrinology, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
Cell Rep. 2023 Aug 29;42(8):112971. doi: 10.1016/j.celrep.2023.112971. Epub 2023 Aug 14.
Fatty acid synthase (FASN) maintains de novo lipogenesis (DNL) to support rapid growth in most proliferating cancer cells. Lipogenic acetyl-coenzyme A (CoA) is primarily produced from carbohydrates but can arise from glutamine-dependent reductive carboxylation. Here, we show that reductive carboxylation also occurs in the absence of DNL. In FASN-deficient cells, reductive carboxylation is mainly catalyzed by isocitrate dehydrogenase-1 (IDH1), but IDH1-generated cytosolic citrate is not utilized for supplying DNL. Metabolic flux analysis (MFA) shows that FASN deficiency induces a net cytosol-to-mitochondria citrate flux through mitochondrial citrate transport protein (CTP). Previously, a similar pathway has been shown to mitigate detachment-induced oxidative stress in anchorage-independent tumor spheroids. We further report that tumor spheroids show reduced FASN activity and that FASN-deficient cells acquire resistance to oxidative stress in a CTP- and IDH1-dependent manner. Collectively, these data indicate that by inducing a cytosol-to-mitochondria citrate flux, anchorage-independent malignant cells can gain redox capacity by trading off FASN-supported rapid growth.
脂肪酸合酶（FASN）维持从头合成（DNL）以支持大多数增殖癌细胞的快速生长。生脂乙酰辅酶 A（CoA）主要由碳水化合物产生，但也可以来自谷氨酰胺依赖性还原羧化。在这里，我们表明，在没有 DNL 的情况下也会发生还原羧化。在 FASN 缺陷细胞中，还原羧化主要由异柠檬酸脱氢酶-1（IDH1）催化，但 IDH1 产生的胞质柠檬酸不用于供应 DNL。代谢通量分析（MFA）表明，FASN 缺乏诱导通过线粒体柠檬酸转运蛋白（CTP）的净细胞质到线粒体柠檬酸通量。以前，已经表明类似的途径可以减轻锚定非依赖性肿瘤球体中分离诱导的氧化应激。我们进一步报告说，肿瘤球体显示出降低的 FASN 活性，并且 FASN 缺陷细胞以 CTP 和 IDH1 依赖性方式获得对氧化应激的抗性。总的来说，这些数据表明，通过诱导细胞质到线粒体柠檬酸通量，锚定非依赖性恶性细胞可以通过牺牲 FASN 支持的快速生长来获得氧化还原能力。
