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

前列腺癌 癌症研究 流浪汉 肌醇 癌症 生物 内科学 医学 受体
作者
Che-Chia Hsu,Guihua Wang,Chien‐Feng Li,Xian Zhang,Zhen Cai,Tingjin Chen,Bo‐Syong Pan,R K Manne,Gagan Deep,Haiwei Gu,Yuzhuo Wang,Danni Peng,Vasudevarao Penugurti,Xiaobo Zhou,Zhigang Xu,Zhong‐Zhu Chen,Ming Chen,Andrew J. Armstrong,Jiaoti Huang,Hong‐yu Li,Hui‐Kuan Lin
出处
期刊:Journal of Experimental Medicine [The Rockefeller University Press]
卷期号:221 (11)
标识
DOI:10.1084/jem.20231832
摘要

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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