文章：

自噬与二酰基甘油酰基转移酶介导的脂滴生物合成联合抑制在急性氨基酸饥饿条件下诱导癌细胞死亡

The Combined Inhibition of Autophagy and Diacylglycerol Acyltransferase-Mediated Lipid Droplet Biogenesis Induces Cancer Cell Death during Acute Amino Acid Starvation

原文发布日期：5 October 2023

DOI: 10.3390/cancers15194857

类型: Article

开放获取: 是

英文摘要：

Lipid droplets (LDs) are dynamic organelles involved in the management of fatty acid trafficking and metabolism. Recent studies suggest that autophagy and LDs serve complementary roles in the protection against nutrient stress, but the autophagy–LD interplay in cancer cells is not well understood. Here, we examined the relationship between autophagy and LDs in starving HeLa cervical cancer- and MDA-MB-231 breast cancer cells. We found that acute amino acid depletion induces autophagy and promotes diacylglycerol acyltransferase 1 (DGAT1)-mediated LD accumulation in HeLa cells. Inhibition of autophagy via late-stage autophagy inhibitors, or by knocking down autophagy-related 5 (ATG5), reduced LD accumulation in amino acid-starved cancer cells, suggesting that autophagy contributes to LD biogenesis. On the contrary, knockdown of adipose triglyceride lipase (ATGL) increased LD accumulation, suggesting that LD breakdown is mediated by lipolysis under these conditions. Concurrent inhibition of autophagy by silencing ATG5 and of LD biogenesis using DGAT inhibitors was effective in killing starving HeLa cells, whereas cell survival was not compromised by suppression of ATGL-mediated lipolysis. Autophagy-dependent LD biogenesis was also observed in the aggressive triple-negative MDA-MB-231 breast cancer cells deprived of amino acids, but these cells were not sensitized to starvation by the combined inhibition of LD biogenesis and autophagy. These findings reveal that while targeting autophagy-driven and DGAT-mediated LD biogenesis reduces the resilience of HeLa cervical cancer cells to amino acid deprivation, this strategy may not be successful in other cancer cell types.

摘要翻译： 

脂滴（LDs）是参与脂肪酸运输与代谢调控的动态细胞器。近期研究表明，自噬与脂滴在应对营养胁迫中发挥互补作用，但二者在癌细胞中的相互作用机制尚不明确。本研究通过饥饿处理的HeLa宫颈癌细胞与MDA-MB-231乳腺癌细胞，系统探讨了自噬与脂滴的关联机制。研究发现，急性氨基酸剥夺可诱导HeLa细胞自噬激活，并促进二酰基甘油酰基转移酶1（DGAT1）介导的脂滴积累。采用晚期自噬抑制剂或敲低自噬相关基因5（ATG5）抑制自噬后，氨基酸饥饿癌细胞中的脂滴积累显著减少，表明自噬参与脂滴生物合成过程。相反，敲低脂肪甘油三酯脂肪酶（ATGL）可增加脂滴积累，提示该条件下脂滴分解主要通过脂解途径实现。同步沉默ATG5抑制自噬与使用DGAT抑制剂阻断脂滴合成，能有效杀伤饥饿处理的HeLa细胞，而抑制ATGL介导的脂解作用则不影响细胞存活。在氨基酸剥夺的三阴性乳腺癌细胞MDA-MB-231中也观察到自噬依赖性脂滴合成现象，但联合抑制脂滴合成与自噬并未增强该细胞对饥饿处理的敏感性。这些发现揭示：虽然靶向自噬驱动及DGAT介导的脂滴合成通路可降低HeLa宫颈癌细胞对氨基酸剥夺的耐受性，但该策略在其他类型癌细胞中可能无法取得同等效果。

原文链接：

The Combined Inhibition of Autophagy and Diacylglycerol Acyltransferase-Mediated Lipid Droplet Biogenesis Induces Cancer Cell Death during Acute Amino Acid Starvation