Department of Immuno-Oncology, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA.
Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
Cell Rep. 2022 May 31;39(9):110870. doi: 10.1016/j.celrep.2022.110870.
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.
克服化疗耐药性仍然是癌症（如三阴性乳腺癌（TNBC））的一个主要未满足的需求。因此，迫切需要进行机制研究以为药物开发提供见解，以克服 TNBC 治疗耐药性。最近，脂肪酸β-氧化（FAO）在化疗耐药性中起着重要作用。但是 FAO 如何通过化疗减轻肿瘤细胞凋亡尚不清楚。在这里，我们表明，升高的 FAO 通过升高的乙酰辅酶 A（CoA）通过乙酰化激活 STAT3。乙酰化 STAT3 上调长链酰基辅酶 A 合成酶 4（ACSL4）的表达，导致磷脂合成增加。升高线粒体膜中的磷脂会导致线粒体完整性增强，从而克服化疗诱导的肿瘤细胞凋亡。相反，在培养的肿瘤细胞和异种移植肿瘤中，通过抑制 ACSL4 或特异性靶向乙酰化-STAT3 增强癌细胞凋亡与线粒体膜内磷脂的减少有关。这项研究表明了肿瘤细胞化疗耐药性的关键机制。
