乙酸盐通过ACSS2介导的乙酰辅酶A驱动卵巢癌静止
Acetate drives ovarian cancer quiescence via ACSS2-mediated acetyl-CoA production
影响因子:6.60000
分区:医学2区 Top / 内分泌学与代谢2区
发表日期:2024 Nov
作者:
Allison C Sharrow, Emily Megill, Amanda J Chen, Afifa Farooqi, Naveen Kumar Tangudu, Apoorva Uboveja, Stacy McGonigal, Nadine Hempel, Nathaniel W Snyder, Ronald J Buckanovich, Katherine M Aird
摘要
静止是传统上被认为与代谢不活跃状态有关的可逆细胞周期退出。肌肉细胞的最新工作表明代谢重编程与静止有关。尚不清楚在癌症中发生代谢变化以驱动静止。我们使用多词方法发现，将乙酸转化为乙酰辅酶A的代谢酶ACSS2在静态的卵巢癌细胞中都高度上调，并且其生存所必需。实际上，静态的卵巢癌细胞具有乙酸衍生的乙酰辅酶A的水平，证实了这些细胞中的ACSS2活性增加。此外，诱导ACSS2表达或补充乙酸细胞足以诱导可逆的静止细胞周期出口。醋酸盐处理细胞的RNA-seq证实了多个细胞周期途径中的负富集，以及在已发表的G0基因特征中富集基因。最后，对患者数据的分析表明，与匹配的原发性肿瘤相比，腹水的肿瘤细胞中的ACSS2表达在腹部的肿瘤细胞上上调。此外，高ACSS2表达与铂耐药性和较差的结果有关。总之，这项研究指出了先前未识别的ACSS2介导的代谢重编程，可在卵巢癌中静止。随着治疗卵巢癌的化学疗法（例如铂）在高度增殖的细胞中具有提高的功效，我们的数据引起了一个有趣的问题，即代谢驱动的静脉可能会影响治疗反应。
Abstract
Quiescence is a reversible cell cycle exit traditionally thought to be associated with a metabolically inactive state. Recent work in muscle cells indicates that metabolic reprogramming is associated with quiescence. Whether metabolic changes occur in cancer to drive quiescence is unclear. Using a multi-omics approach, we found that the metabolic enzyme ACSS2, which converts acetate into acetyl-CoA, is both highly upregulated in quiescent ovarian cancer cells and required for their survival. Indeed, quiescent ovarian cancer cells have increased levels of acetate-derived acetyl-CoA, confirming increased ACSS2 activity in these cells. Furthermore, either inducing ACSS2 expression or supplementing cells with acetate was sufficient to induce a reversible quiescent cell cycle exit. RNA-Seq of acetate treated cells confirmed negative enrichment in multiple cell cycle pathways as well as enrichment of genes in a published G0 gene signature. Finally, analysis of patient data showed that ACSS2 expression is upregulated in tumor cells from ascites, which are thought to be more quiescent, compared to matched primary tumors. Additionally, high ACSS2 expression is associated with platinum resistance and worse outcomes. Together, this study points to a previously unrecognized ACSS2-mediated metabolic reprogramming that drives quiescence in ovarian cancer. As chemotherapies to treat ovarian cancer, such as platinum, have increased efficacy in highly proliferative cells, our data give rise to the intriguing question that metabolically-driven quiescence may affect therapeutic response.