• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

IMP A1 衍生的肌醇通过 IMPDH2 的激活来维持去势抵抗性前列腺癌的干性。

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

机构信息

Department of Pathology, Duke University Medical Center, Duke University School of Medicine, Durham, NC, USA.

Department of Cancer Biology, Wake Forest Baptist Medical Center, Wake Forest University, Winston Salem, NC, USA.

出版信息

J Exp Med. 2024 Nov 4;221(11). doi: 10.1084/jem.20231832. Epub 2024 Oct 29.

DOI:10.1084/jem.20231832
PMID:39470689
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11528126/
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.

摘要

在雄激素剥夺疗法 (ABT) 期间获得的前列腺癌干细胞 (PCSCs) 有助于导致去势抵抗性前列腺癌 (CRPC)。然而，对于严格协调这一过程的特定代谢物知之甚少。在这里，我们表明，PCSCs 中富含肌醇的 IMPA1 衍生的肌醇是一种关键代谢物，对于维持 PCSCs 用于 CRPC 进展和 ABT 耐药性至关重要。值得注意的是，前列腺中的条件性 Impa1 敲除会破坏 PCSCs 的池和特性，以协调 CRPC 进展并延长 TRAMP 小鼠的存活时间。IMPA1 衍生的肌醇作为辅因子，可直接结合并激活 IMPDH2，后者合成鸟苷酸核苷酸，用于维持具有 ARlow/- 特征的 PCSCs，从而导致 CRPC 进展和 ABT 耐药性。IMPDA1/肌醇/IMPDH2 轴在人前列腺癌中上调，其过表达预示着预后不良。通过遗传和药理学靶向 IMPA1/肌醇/IMPDH2 轴，可在各种 CRPC 异种移植瘤、患者来源的异种移植瘤 (PDX) 肿瘤模型和 TRAMP 小鼠模型中消除 CRPC 并克服 ABT 耐药性。我们的研究确定了 IMPDH2 作为肌醇传感器，其肌醇激活代表了维持 PCSCs 用于 CRPC 和 ABT 耐药性的关键机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f307/11528126/ba3c178486a6/JEM_20231832_Fig10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f307/11528126/b2736b23e3cc/JEM_20231832_GA.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f307/11528126/60b0f2b88bd3/JEM_20231832_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f307/11528126/b60da4d46920/JEM_20231832_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f307/11528126/95395f381d36/JEM_20231832_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f307/11528126/3455477c2007/JEM_20231832_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f307/11528126/edf4b36613c4/JEM_20231832_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f307/11528126/063446d273a8/JEM_20231832_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f307/11528126/951982330706/JEM_20231832_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f307/11528126/33c3ef53043d/JEM_20231832_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f307/11528126/00a750332730/JEM_20231832_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f307/11528126/10e4ac2b4750/JEM_20231832_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f307/11528126/66aee24c686a/JEM_20231832_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f307/11528126/5bc553c00c82/JEM_20231832_Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f307/11528126/07b1d2df5d2b/JEM_20231832_FigS5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f307/11528126/a454b483a0e3/JEM_20231832_Fig9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f307/11528126/ba3c178486a6/JEM_20231832_Fig10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f307/11528126/b2736b23e3cc/JEM_20231832_GA.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f307/11528126/60b0f2b88bd3/JEM_20231832_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f307/11528126/b60da4d46920/JEM_20231832_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f307/11528126/95395f381d36/JEM_20231832_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f307/11528126/3455477c2007/JEM_20231832_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f307/11528126/edf4b36613c4/JEM_20231832_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f307/11528126/063446d273a8/JEM_20231832_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f307/11528126/951982330706/JEM_20231832_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f307/11528126/33c3ef53043d/JEM_20231832_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f307/11528126/00a750332730/JEM_20231832_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f307/11528126/10e4ac2b4750/JEM_20231832_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f307/11528126/66aee24c686a/JEM_20231832_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f307/11528126/5bc553c00c82/JEM_20231832_Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f307/11528126/07b1d2df5d2b/JEM_20231832_FigS5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f307/11528126/a454b483a0e3/JEM_20231832_Fig9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f307/11528126/ba3c178486a6/JEM_20231832_Fig10.jpg

相似文献

1
IMPA1-derived inositol maintains stemness in castration-resistant prostate cancer via IMPDH2 activation.IMP A1 衍生的肌醇通过 IMPDH2 的激活来维持去势抵抗性前列腺癌的干性。
J Exp Med. 2024 Nov 4;221(11). doi: 10.1084/jem.20231832. Epub 2024 Oct 29.
2
AGD1/USP10/METTL13 complexes enhance cancer stem cells proliferation and diminish the therapeutic effect of docetaxel via CD44 m6A modification in castration resistant prostate cancer.AGD1/USP10/METTL13复合物通过对去势抵抗性前列腺癌中CD44进行m6A修饰来增强癌症干细胞增殖并降低多西他赛的治疗效果。
J Exp Clin Cancer Res. 2025 Jan 14;44(1):12. doi: 10.1186/s13046-025-03272-3.
3
Nuclear receptor TLX functions to promote cancer stemness and EMT in prostate cancer via its direct transactivation of CD44 and stem cell-regulatory transcription factors.核受体 TLX 通过其对 CD44 和干细胞调节转录因子的直接反式激活，促进前列腺癌中的癌症干性和 EMT。
Br J Cancer. 2024 Nov;131(9):1450-1462. doi: 10.1038/s41416-024-02843-z. Epub 2024 Sep 26.
4
Nuclear receptor profiling in prostatospheroids and castration-resistant prostate cancer.前列腺小体和去势抵抗性前列腺癌中的核受体谱分析。
Endocr Relat Cancer. 2018 Jan;25(1):35-50. doi: 10.1530/ERC-17-0280. Epub 2017 Oct 17.
5
Endothelial nitric oxide synthase (eNOS)-NO signaling axis functions to promote the growth of prostate cancer stem-like cells.内皮型一氧化氮合酶（eNOS）-NO 信号轴的功能是促进前列腺癌干细胞样细胞的生长。
Stem Cell Res Ther. 2022 May 7;13(1):188. doi: 10.1186/s13287-022-02864-6.
6
MYO6 contributes to tumor progression and enzalutamide resistance in castration-resistant prostate cancer by activating the focal adhesion signaling pathway.MYO6 通过激活粘着斑信号通路促进去势抵抗性前列腺癌的肿瘤进展和恩杂鲁胺耐药性。
Cell Commun Signal. 2024 Oct 24;22(1):517. doi: 10.1186/s12964-024-01897-z.
7
Orphan nuclear receptor TLX contributes to androgen insensitivity in castration-resistant prostate cancer via its repression of androgen receptor transcription.孤儿核受体 TLX 通过抑制雄激素受体转录促进去势抵抗性前列腺癌的雄激素不敏感。
Oncogene. 2018 Jun;37(25):3340-3355. doi: 10.1038/s41388-018-0198-z. Epub 2018 Mar 20.
8
Targeting the KIF4A/AR Axis to Reverse Endocrine Therapy Resistance in Castration-resistant Prostate Cancer.靶向 KIF4A/AR 轴逆转去势抵抗性前列腺癌的内分泌治疗耐药性。
Clin Cancer Res. 2020 Mar 15;26(6):1516-1528. doi: 10.1158/1078-0432.CCR-19-0396. Epub 2019 Dec 3.
9
Patient-derived Hormone-naive Prostate Cancer Xenograft Models Reveal Growth Factor Receptor Bound Protein 10 as an Androgen Receptor-repressed Gene Driving the Development of Castration-resistant Prostate Cancer.患者来源的激素敏感型前列腺癌异种移植模型揭示生长因子受体结合蛋白 10 作为雄激素受体抑制基因，驱动去势抵抗性前列腺癌的发展。
Eur Urol. 2018 Jun;73(6):949-960. doi: 10.1016/j.eururo.2018.02.019. Epub 2018 Mar 12.
10
A Constitutive Intrinsic Inflammatory Signaling Circuit Composed of miR-196b, Meis2, PPP3CC, and p65 Drives Prostate Cancer Castration Resistance.由miR-196b、Meis2、PPP3CC和p65组成的组成型内在炎症信号通路驱动前列腺癌去势抵抗。
Mol Cell. 2017 Jan 5;65(1):154-167. doi: 10.1016/j.molcel.2016.11.034. Epub 2016 Dec 29.

引用本文的文献

1
Glucose metabolism and its direct action in cancer and immune regulation: opportunities and challenges for metabolic targeting.葡萄糖代谢及其在癌症和免疫调节中的直接作用：代谢靶向的机遇与挑战
J Biomed Sci. 2025 Jul 29;32(1):71. doi: 10.1186/s12929-025-01167-1.
2
ALDH4A1 functions as an active component of the MPC complex maintaining mitochondrial pyruvate import for TCA cycle entry and tumour suppression.醛脱氢酶4A1（ALDH4A1）作为线粒体丙酮酸载体（MPC）复合物的活性成分，维持线粒体丙酮酸的导入，以进入三羧酸循环（TCA）并发挥肿瘤抑制作用。
Nat Cell Biol. 2025 May;27(5):847-862. doi: 10.1038/s41556-025-01651-8. Epub 2025 May 12.

本文引用的文献

1
Human organoids in basic research and clinical applications.人类器官类器官在基础研究和临床应用中的应用。
Signal Transduct Target Ther. 2022 May 24;7(1):168. doi: 10.1038/s41392-022-01024-9.
2
Identification of myo-inositol-binding proteins by using the biotin pull-down strategy in cultured cells.利用细胞培养中的生物素下拉技术鉴定肌醇结合蛋白。
STAR Protoc. 2022 May 14;3(2):101385. doi: 10.1016/j.xpro.2022.101385. eCollection 2022 Jun 17.
3
IMPDH dysregulation in disease: a mini review.疾病中 IMPDH 的失调：小型综述。
Biochem Soc Trans. 2022 Feb 28;50(1):71-82. doi: 10.1042/BST20210446.
4
Inositol serves as a natural inhibitor of mitochondrial fission by directly targeting AMPK.肌醇通过直接靶向 AMPK 充当线粒体分裂的天然抑制剂。
Mol Cell. 2021 Sep 16;81(18):3803-3819.e7. doi: 10.1016/j.molcel.2021.08.025.
5
Drugging the "Undruggable" MYCN Oncogenic Transcription Factor: Overcoming Previous Obstacles to Impact Childhood Cancers.靶向“不可成药”的 MYCN 致癌转录因子：克服先前的障碍以影响儿童癌症。
Cancer Res. 2021 Apr 1;81(7):1627-1632. doi: 10.1158/0008-5472.CAN-20-3108. Epub 2021 Jan 28.
6
Differential expression of αVβ3 and αVβ6 integrins in prostate cancer progression.αVβ3和αVβ6整合素在前列腺癌进展中的差异表达。
PLoS One. 2021 Jan 22;16(1):e0244985. doi: 10.1371/journal.pone.0244985. eCollection 2021.
7
Human organoids: model systems for human biology and medicine.人类类器官：人类生物学和医学的模型系统。
Nat Rev Mol Cell Biol. 2020 Oct;21(10):571-584. doi: 10.1038/s41580-020-0259-3. Epub 2020 Jul 7.
8
Combined TP53 and RB1 Loss Promotes Prostate Cancer Resistance to a Spectrum of Therapeutics and Confers Vulnerability to Replication Stress.联合 TP53 和 RB1 缺失促进前列腺癌对多种治疗药物的耐药性，并导致对复制应激的易感性。
Cell Rep. 2020 May 26;31(8):107669. doi: 10.1016/j.celrep.2020.107669.
9
Metabolic reprogramming and cancer progression.代谢重编程与癌症进展。
Science. 2020 Apr 10;368(6487). doi: 10.1126/science.aaw5473.
10
Lactate Is a Natural Suppressor of RLR Signaling by Targeting MAVS.乳酸通过靶向 MAVS 抑制 RLR 信号。
Cell. 2019 Jun 27;178(1):176-189.e15. doi: 10.1016/j.cell.2019.05.003. Epub 2019 May 30.