Acetate utilization promotes hormone therapy resistance in prostate cancer through neuroendocrine differentiation

IF 15.8 1区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Resistance Updates Pub Date : 2024-10-06 DOI:10.1016/j.drup.2024.101158

Dajun Gao , Yanting Shen , Lingfan Xu , Yi Sun , Hailiang Hu , Bin Xu , Zhong Wang , Huan Xu

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引用次数: 0

Abstract

Aims

Tumor fatty acid (FA) metabolic plasticity plays a pivotal role in resistance to therapy and poses limitations to anticancer strategies. In this study, our aim is to uncover the role of acetate metabolism in neurodifferentiation (NED)-mediated castration-resistant prostate cancer (CRPC).

Methods

We conducted analyses using LC-MS/MS on clinical prostate cancer tissue before and after hormone therapy. We established tumor xenograft mouse models, primary tumor cells, and human-derived organoids to detect the novel mechanism of NED and to identify potential therapies.

Results

The hormone therapy-induced upregulation of acetate metabolism was mediated by acyl-CoA synthetase short-chain family member 2 (ACSS2), which increased c-MYC expression for NED induction. Notably, combined treatment with an ACSS2 inhibitor and enzalutamide significantly reduced the xenograft tumor volume.

Conclusion

Our findings uncovered the critical role of acetate metabolism in NED-mediated CRPC and suggest that ACSS2 inhibitors may represent a novel, low-toxicity strategy when combined with hormone therapy for treating patients with NED-mediated CRPC.

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乙酸利用通过神经内分泌分化促进前列腺癌对激素疗法的耐受性

目的肿瘤脂肪酸（FA）代谢的可塑性在耐药性中起着关键作用，并对抗癌策略造成限制。在本研究中，我们的目的是揭示乙酸盐代谢在神经分化（NED）介导的阉割耐药前列腺癌（CRPC）中的作用。结果激素治疗诱导的醋酸代谢上调是由酰基-CoA合成酶短链家族成员2（ACSS2）介导的，它增加了c-MYC的表达，从而诱导了NED。值得注意的是，ACSS2抑制剂和恩杂鲁胺联合治疗可显著减少异种移植肿瘤的体积。结论我们的研究结果揭示了乙酸盐代谢在NED介导的CRPC中的关键作用，并表明ACSS2抑制剂与激素疗法联合治疗NED介导的CRPC患者可能是一种新型、低毒的策略。

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

Drug Resistance Updates 医学-药学

CiteScore

26.20

自引率

11.90%

发文量

审稿时长

29 days

期刊介绍： Drug Resistance Updates serves as a platform for publishing original research, commentary, and expert reviews on significant advancements in drug resistance related to infectious diseases and cancer. It encompasses diverse disciplines such as molecular biology, biochemistry, cell biology, pharmacology, microbiology, preclinical therapeutics, oncology, and clinical medicine. The journal addresses both basic research and clinical aspects of drug resistance, providing insights into novel drugs and strategies to overcome resistance. Original research articles are welcomed, and review articles are authored by leaders in the field by invitation. Articles are written by leaders in the field, in response to an invitation from the Editors, and are peer-reviewed prior to publication. Articles are clear, readable, and up-to-date, suitable for a multidisciplinary readership and include schematic diagrams and other illustrations conveying the major points of the article. The goal is to highlight recent areas of growth and put them in perspective. *Expert reviews in clinical and basic drug resistance research in oncology and infectious disease *Describes emerging technologies and therapies, particularly those that overcome drug resistance *Emphasises common themes in microbial and cancer research