IMPA1-derived inositol maintains stemness in castration-resistant prostate cancer via IMPDH2 activation.

IF 12.6 1区医学 Q1 IMMUNOLOGY Journal of Experimental Medicine Pub Date : 2024-11-04 Epub Date: 2024-10-29 DOI:10.1084/jem.20231832

Che-Chia Hsu, Guihua Wang, Chien-Feng Li, Xian Zhang, Zhen Cai, Tingjin Chen, Bo-Syong Pan, Rajesh Kumar Manne, Gagan Deep, Haiwei Gu, Yuzhuo Wang, Danni Peng, Vasudevarao Penugurti, Xiaobo Zhou, Zhigang Xu, Zhongzhu Chen, Ming Chen, Andrew J Armstrong, Jiaoti Huang, Hong-Yu Li, Hui-Kuan Lin

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Abstract

Acquisition of prostate cancer stem cells (PCSCs) manifested during androgen ablation therapy (ABT) contributes to castration-resistant prostate cancer (CRPC). However, little is known about the specific metabolites critically orchestrating this process. Here, we show that IMPA1-derived inositol enriched in PCSCs is a key metabolite crucially maintaining PCSCs for CRPC progression and ABT resistance. Notably, conditional Impa1 knockout in the prostate abrogates the pool and properties of PCSCs to orchestrate CRPC progression and prolong the survival of TRAMP mice. IMPA1-derived inositol serves as a cofactor that directly binds to and activates IMPDH2, which synthesizes guanylate nucleotides for maintaining PCSCs with ARlow/- features leading to CRPC progression and ABT resistance. IMPA1/inositol/IMPDH2 axis is upregulated in human prostate cancer, and its overexpression predicts poor survival outcomes. Genetically and pharmacologically targeting the IMPA1/inositol/IMPDH2 axis abrogates CRPC and overcomes ABT resistance in various CRPC xenografts, patient-derived xenograft (PDX) tumor models, and TRAMP mouse models. Our study identifies IMPDH2 as an inositol sensor whose activation by inositol represents a key mechanism for maintaining PCSCs for CRPC and ABT resistance.

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IMPA1衍生肌醇通过激活IMPDH2维持耐受性前列腺癌的干性。

雄激素消融治疗（ABT）期间前列腺癌干细胞（PCSCs）的获得是导致阉割耐药前列腺癌（CRPC）的原因之一。然而，人们对协调这一过程的特定代谢物知之甚少。在这里，我们发现 PCSCs 中富含的 IMPA1 衍生肌醇是一种关键的代谢物，对维持 PCSCs 的 CRPC 进展和 ABT 抗性至关重要。值得注意的是，有条件地敲除前列腺中的IMPA1会削弱PCSCs的数量和特性，使其无法协调CRPC的进展并延长TRAMP小鼠的存活时间。IMPA1衍生的肌醇是一种辅助因子，可直接与IMPDH2结合并激活IMPDH2，后者可合成鸟苷酸核苷酸，以维持具有ARlow/-特征的PCSCs，从而导致CRPC进展和ABT耐药。IMPA1/肌醇/IMPDH2轴在人类前列腺癌中上调，其过度表达预示着不良的生存结果。通过基因和药物靶向 IMPA1/肌醇/IMPDH2轴，可在各种CRPC异种移植、患者衍生异种移植（PDX）肿瘤模型和TRAMP小鼠模型中消减CRPC并克服ABT耐药性。我们的研究发现，IMPDH2是一种肌醇传感器，肌醇对它的激活是维持PCSCs对CRPC和ABT耐药的关键机制。

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

Journal of Experimental Medicine 医学-免疫学

CiteScore

26.60

自引率

1.30%

发文量

189

审稿时长

3-8 weeks

期刊介绍： Since its establishment in 1896, the Journal of Experimental Medicine (JEM) has steadfastly pursued the publication of enduring and exceptional studies in medical biology. In an era where numerous publishing groups are introducing specialized journals, we recognize the importance of offering a distinguished platform for studies that seamlessly integrate various disciplines within the pathogenesis field. Our unique editorial system, driven by a commitment to exceptional author service, involves two collaborative groups of editors: professional editors with robust scientific backgrounds and full-time practicing scientists. Each paper undergoes evaluation by at least one editor from both groups before external review. Weekly editorial meetings facilitate comprehensive discussions on papers, incorporating external referee comments, and ensure swift decisions without unnecessary demands for extensive revisions. Encompassing human studies and diverse in vivo experimental models of human disease, our focus within medical biology spans genetics, inflammation, immunity, infectious disease, cancer, vascular biology, metabolic disorders, neuroscience, and stem cell biology. We eagerly welcome reports ranging from atomic-level analyses to clinical interventions that unveil new mechanistic insights.