细胞凋亡
线粒体
乙酰化
癌症研究
癌细胞
细胞
生物
β氧化
癌症
脂肪酸
化学
细胞生物学
生物化学
遗传学
基因
作者
Yijia Li,Johannes F. Fahrmann,Maryam Aftabizadeh,Qianqian Zhao,Satyendra Chandra Tripathi,Chunyan Zhang,Yuan Yuan,David K. Ann,Samir Hanash,Hua Yu
出处
期刊:Cell Reports
[Elsevier]
日期:2022-05-01
卷期号:39 (9): 110870-110870
被引量:35
标识
DOI:10.1016/j.celrep.2022.110870
摘要
Overcoming resistance to chemotherapies remains a major unmet need for cancers, such as triple-negative breast cancer (TNBC). Therefore, mechanistic studies to provide insight for drug development are urgently needed to overcome TNBC therapy resistance. Recently, an important role of fatty acid β-oxidation (FAO) in chemoresistance has been shown. But how FAO might mitigate tumor cell apoptosis by chemotherapy is unclear. Here, we show that elevated FAO activates STAT3 by acetylation via elevated acetyl-coenzyme A (CoA). Acetylated STAT3 upregulates expression of long-chain acyl-CoA synthetase 4 (ACSL4), resulting in increased phospholipid synthesis. Elevating phospholipids in mitochondrial membranes leads to heightened mitochondrial integrity, which in turn overcomes chemotherapy-induced tumor cell apoptosis. Conversely, in both cultured tumor cells and xenograft tumors, enhanced cancer cell apoptosis by inhibiting ASCL4 or specifically targeting acetylated-STAT3 is associated with a reduction in phospholipids within mitochondrial membranes. This study demonstrates a critical mechanism underlying tumor cell chemoresistance.
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