Fatty Acid Metabolism Provides an Essential Survival Signal in OxPhos and BCR DLBCL Cells.

IF 3.9 3区 工程技术 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Aurélie Montagne, Konstantina Kotta, Karoline Kielbassa-Elkadi, Isabelle Martins, José Ángel Martinez-Climent, Guido Kroemer, Catherine Thieblemont, Véronique Baud
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引用次数: 0

Abstract

Backgroung/objectives: Diffuse large B-cell lymphoma (DLBCL) is the most frequent subtype of malignant lymphoma and is a heterogeneous disease with various gene and chromosomal abnormalities. The development of novel therapeutic treatments has improved DLBCL prognosis, but patients with early relapse or refractory disease have a poor outcome (with a mortality of around 40%). Metabolic reprogramming is a hallmark of cancer cells. Fatty acid (FA) metabolism is frequently altered in cancer cells and recently emerged as a critical survival path for cancer cell survival. Methods: We first performed the metabolic characterization of an extended panel of DLBCL cell lines, including lipid droplet content. Then, we investigated the effect of drugs targeting FA metabolism on DLBCL cell survival. Further, we studied how the combination of drugs targeting FA and either mitochondrial metabolism or mTOR pathway impacts on DLBCL cell death. Results: Here, we reveal, using a large panel of DLBCL cell lines characterized by their metabolic status, that targeting of FA metabolism induces massive DLBCL cell death regardless of their OxPhos or BCR/glycolytic subtype. Further, FA drives resistance of DLBCL cell death induced by mitochondrial stress upon treatment with either metformin or L-asparaginase, two FDA-approved antimetabolic drugs. Interestingly, combining inhibition of FA metabolism with that of the mTOR oncogenic pathway strongly potentiates DLBCL cell death. Conclusion: Altogether, our data highlight the central role played by FA metabolism in DLBCL cell survival, independently of their metabolic subtype, and provide the framework for the use of drugs targeting this metabolic vulnerability to overcome resistance in DLBCL patients.

脂肪酸代谢在OxPhos和BCR DLBCL细胞中提供必要的生存信号。
背景/目的:弥漫性大b细胞淋巴瘤(DLBCL)是恶性淋巴瘤中最常见的亚型,是一种具有多种基因和染色体异常的异质性疾病。新型治疗方法的发展改善了DLBCL的预后,但早期复发或难治性疾病的患者预后较差(死亡率约为40%)。代谢重编程是癌细胞的一个特征。脂肪酸(FA)代谢在癌细胞中经常发生改变,最近成为癌细胞生存的关键途径。方法:我们首先对一组扩展的DLBCL细胞系进行了代谢表征,包括脂滴含量。然后,我们研究了靶向FA代谢的药物对DLBCL细胞存活的影响。此外,我们研究了靶向FA的药物与线粒体代谢或mTOR途径的联合如何影响DLBCL细胞死亡。结果:在这里,我们发现,使用大量具有代谢状态特征的DLBCL细胞系,靶向FA代谢诱导大量DLBCL细胞死亡,无论其OxPhos或BCR/糖酵解亚型。此外,FA在二甲双胍或l -天冬酰胺酶(两种fda批准的抗代谢药物)治疗后,驱动线粒体应激诱导的DLBCL细胞死亡的耐药性。有趣的是,FA代谢抑制与mTOR致癌途径的联合抑制强烈增强了DLBCL细胞的死亡。结论:总的来说,我们的数据强调了FA代谢在DLBCL细胞存活中的核心作用,独立于其代谢亚型,并为使用针对这种代谢易感的药物来克服DLBCL患者的耐药提供了框架。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Biomedicines
Biomedicines Biochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology
CiteScore
5.20
自引率
8.50%
发文量
2823
审稿时长
8 weeks
期刊介绍: Biomedicines (ISSN 2227-9059; CODEN: BIOMID) is an international, scientific, open access journal on biomedicines published quarterly online by MDPI.
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