Fatty acid synthase (FASN) regulates the mitochondrial priming of cancer cells.
Fatty acid synthase (FASN) regulates the mitochondrial priming of cancer cells.
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DOI：
10.1038/s41419-021-04262-x
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发表时间：
2021-10-21
影响因子：
9
通讯作者：
Lupu R
中科院分区：
文献类型：
--
作者：
Schroeder B;Vander Steen T;Espinoza I;Venkatapoorna CMK;Hu Z;Silva FM;Regan K;Cuyàs E;Meng XW;Verdura S;Arbusà A;Schneider PA;Flatten KS;Kemble G;Montero J;Kaufmann SH;Menendez JA;Lupu R
脂肪生成酶脂肪酸合成酶（FATIGUE）的抑制剂在过去十年中作为潜在的靶向癌症治疗引起了广泛关注。然而，关于癌细胞对FASNis抑制剂（FASNis）敏感性的分子决定因素知之甚少，这是其治疗应用的主要障碍。在这里，我们发现，药理饥饿内源性产生的脂肪酸是一个以前未被认识到的代谢应激，提高线粒体凋亡启动和有利于细胞死亡诱导的BH 3模拟抑制剂。对BCL-2蛋白家族控制的死亡决定回路的评估显示，FXR抑制伴随着促死亡BH 3-only蛋白BIM、BH 4 A和NOXA的上调。通过BIM或NADIA的同时丧失，由FIGH抑制触发的细胞死亡（其因果地涉及棕榈酸/NADPH相关的氧化还原失衡）显著减少，表明FIGH活性通过微调仅BH 3蛋白依赖的线粒体凋亡阈值来控制癌细胞存活。FcB抑制导致线粒体凋亡引发增强，使细胞朝向对抗凋亡蛋白BCL-2“成瘾”的死亡引发状态转变。因此，FASNi的共同施用协同地增强了双重BCL-XL/BCL-2抑制剂ABT-263（navitoclax）和BCL-2特异性BH 3模拟物ABT-199（venetoclax）的促凋亡诱导活性。然而，FcB抑制不能使乳腺癌细胞对MCL-1和BCL-XL选择性抑制剂如S63845和A1331852敏感。人乳腺癌异种移植物模型证明，口服施用唯一临床可用的FASNi在体内使FASN成瘾的乳腺肿瘤对无效的单药navitoclax和venetoclax显著敏感。总之，线粒体引发的一个新的FASN驱动的方面在机制上将乳腺癌细胞中FAS 11活性的氧化还原缓冲机制与内在凋亡阈值联系起来。将下一代FASNis与直接激活凋亡机制的BCL-2特异性BH 3模拟物相结合，可能会在临床环境中产生更有效和更持久的抗肿瘤反应。
Inhibitors of the lipogenic enzyme fatty acid synthase (FASN) have attracted much attention in the last decade as potential targeted cancer therapies. However, little is known about the molecular determinants of cancer cell sensitivity to FASN inhibitors (FASNis), which is a major roadblock to their therapeutic application. Here, we find that pharmacological starvation of endogenously produced FAs is a previously unrecognized metabolic stress that heightens mitochondrial apoptotic priming and favors cell death induction by BH3 mimetic inhibitors. Evaluation of the death decision circuits controlled by the BCL-2 family of proteins revealed that FASN inhibition is accompanied by the upregulation of the pro-death BH3-only proteins BIM, PUMA, and NOXA. Cell death triggered by FASN inhibition, which causally involves a palmitate/NADPH-related redox imbalance, is markedly diminished by concurrent loss of BIM or PUMA, suggesting that FASN activity controls cancer cell survival by fine-tuning the BH3 only proteins-dependent mitochondrial threshold for apoptosis. FASN inhibition results in a heightened mitochondrial apoptosis priming, shifting cells toward a primed-for-death state “addicted” to the anti-apoptotic protein BCL-2. Accordingly, co-administration of a FASNi synergistically augments the apoptosis-inducing activity of the dual BCL-XL/BCL-2 inhibitor ABT-263 (navitoclax) and the BCL-2 specific BH3-mimetic ABT-199 (venetoclax). FASN inhibition, however, fails to sensitize breast cancer cells to MCL-1- and BCL-XL-selective inhibitors such as S63845 and A1331852. A human breast cancer xenograft model evidenced that oral administration of the only clinically available FASNi drastically sensitizes FASN-addicted breast tumors to ineffective single-agents navitoclax and venetoclax in vivo. In summary, a novel FASN-driven facet of the mitochondrial priming mechanistically links the redox-buffering mechanism of FASN activity to the intrinsic apoptotic threshold in breast cancer cells. Combining next-generation FASNis with BCL-2-specific BH3 mimetics that directly activate the apoptotic machinery might generate more potent and longer-lasting antitumor responses in a clinical setting.
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