<i>De novo</i> lipogenesis at the mitotic exit is used for nuclear envelope reassembly/expansion. Implications for combined chemotherapy
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Mitosis has been traditionally considered a metabolically inactive phase. We have previously shown, however, that extensive alterations in lipids occur as the cells traverse mitosis, including increased <i>de novo</i> fatty acid (FA) and phosphatidylcholine (PtdCho) synthesis and decreased lysophospholipid content. Given the diverse structural and functional properties of these lipids, we sought to study their metabolic fate and their importance for cell cycle completion. Here we show that FA and PtdCho synthesized at the mitotic exit are destined to the nuclear envelope. Importantly, FA and PtdCho synthesis, but not the decrease in lysophospholipid content, are necessary for cell cycle completion beyond G<sub>2</sub>/M. Moreover, the presence of alternative pathways for PtdCho synthesis renders the cells less sensitive to its inhibition than to the impairment of FA synthesis. FA synthesis, thus, represents a cell cycle-related metabolic vulnerability that could be exploited for combined chemotherapy. We explored the combination of fatty acid synthase (FASN) inhibition with agents that act at different phases of the cell cycle. Our results show that the effect of FASN inhibition may be enhanced under some drug combinations.
长期以来，有丝分裂（Mitosis）一直被视为代谢不活跃的阶段。然而，我们此前的研究表明，细胞在经历有丝分裂的过程中会发生广泛的脂质改变，包括从头（de novo）合成脂肪酸（fatty acid, FA）与磷脂酰胆碱（phosphatidylcholine, PtdCho），以及溶血磷脂（lysophospholipid）含量的降低。鉴于这些脂质具有多样的结构与功能特性，我们旨在探究其代谢命运及其对细胞周期完成的重要性。本研究证实，有丝分裂期合成的脂肪酸与磷脂酰胆碱最终会靶向聚集于核被膜（nuclear envelope）。值得注意的是，脂肪酸与磷脂酰胆碱的合成——而非溶血磷脂含量的降低——是细胞周期越过G₂/M期完成的必要条件。此外，由于存在磷脂酰胆碱合成的替代途径，细胞对磷脂酰胆碱合成抑制的敏感性要低于对脂肪酸合成受损的敏感性。因此，脂肪酸合成代表了一种与细胞周期相关的代谢脆弱性，可被应用于联合化疗的开发。我们探索了脂肪酸合酶（fatty acid synthase, FASN）抑制剂与作用于细胞周期不同时相的药物的联合使用策略。研究结果显示，在部分联合用药方案下，脂肪酸合酶抑制剂的作用效果可得到增强。
