Targeting ketone body metabolism in mitigating gemcitabine resistance.

IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Krizia Rohena-Rivera, Sungyong You, Minhyung Kim, Sandrine Billet, Johanna Ten Hoeve, Gabrielle Gonzales, Chengqun Huang, Ashley Heard, Keith Syson Chan, Neil A Bhowmick
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引用次数: 0

Abstract

Chemotherapy is often combined with surgery for muscle invasive and nonmuscle invasive bladder cancer (BCa). However, 70% of the patients recur within 5 years. Metabolic reprogramming is an emerging hallmark in cancer chemoresistance. Here, we report a gemcitabine resistance mechanism that promotes cancer reprogramming via the metabolic enzyme OXCT1. This mitochondrial enzyme, responsible for the rate-limiting step in β-hydroxybutyrate (βHB) catabolism, was elevated in muscle invasive disease and in patients with chemoresistant BCa. Resistant orthotopic tumors presented an OXCT1-dependent rise in mitochondrial oxygen consumption rate, ATP, and nucleotide biosynthesis. In resistant BCa, knocking out OXCT1 restored gemcitabine sensitivity, and administering the nonmetabolizable βHB enantiomer (S-βHB) only partially restored gemcitabine sensitivity. Suggesting an extrametabolic role for OXCT1, multi-omics analysis of gemcitabine sensitive and resistant cells revealed an OXCT1-dependent signature with the transcriptional repressor OVOL1 as a master regulator of epithelial differentiation. The elevation of OVOL1 target genes was associated with its cytoplasmic translocation and poor prognosis in a cohort of patients with BCa who have been treated with chemotherapy. The KO of OXCT1 restored OVOL1 transcriptional repressive activity by its nuclear translocation. Orthotopic mouse models of BCa supported OXCT1 as a mediator of gemcitabine sensitivity through ketone metabolism and regulating cancer stem cell differentiation.

针对酮体代谢缓解吉西他滨耐药性。
对于肌层浸润性和非肌层浸润性膀胱癌,化疗通常与手术相结合。然而,70%的患者会在5年内复发。代谢重编程是癌症化疗耐药性的一个新特征。在这里,我们报告了一种吉西他滨耐药机制,它通过代谢酶 OXCT1 促进癌症重编程。这种线粒体酶负责β-羟丁酸(βHB)分解代谢的限速步骤,在肌肉浸润性疾病和化疗耐药的膀胱癌患者中升高。耐药性正位肿瘤的线粒体耗氧率、ATP 和核苷酸生物合成的增加依赖于 OXCT1。在耐药性膀胱癌中,敲除 OXCT1 可恢复吉西他滨的敏感性,而服用不可代谢的 βHB,对映体(S-βHB)只能部分恢复吉西他滨的敏感性。对吉西他滨敏感细胞和耐药细胞进行的多组学分析显示,OXCT1依赖于转录抑制因子OVOL1,而OVOL1是上皮分化的主调节因子。在化疗的 BCa 患者群中,OVOL1 靶基因的升高与其胞质易位和不良预后有关。敲除OXCT1可通过其核转位恢复OVOL1的转录抑制活性。膀胱癌原位小鼠模型支持 OXCT1 通过酮代谢和调节癌症干细胞分化成为吉西他滨敏感性的介质。
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来源期刊
JCI insight
JCI insight Medicine-General Medicine
CiteScore
13.70
自引率
1.20%
发文量
543
审稿时长
6 weeks
期刊介绍: JCI Insight is a Gold Open Access journal with a 2022 Impact Factor of 8.0. It publishes high-quality studies in various biomedical specialties, such as autoimmunity, gastroenterology, immunology, metabolism, nephrology, neuroscience, oncology, pulmonology, and vascular biology. The journal focuses on clinically relevant basic and translational research that contributes to the understanding of disease biology and treatment. JCI Insight is self-published by the American Society for Clinical Investigation (ASCI), a nonprofit honor organization of physician-scientists founded in 1908, and it helps fulfill the ASCI's mission to advance medical science through the publication of clinically relevant research reports.
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