Faculty, Staff and Student Publications

Language

English

Publication Date

11-4-2024

Journal

Journal of Experimental Medicine

DOI

10.1084/jem.20231832

PMID

39470689

PMCID

PMC11528126

PubMedCentral® Posted Date

10-29-2024

PubMedCentral® Full Text Version

Post-print

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.

Keywords

Animals, Male, Humans, Mice, Prostatic Neoplasms, Castration-Resistant, Neoplastic Stem Cells, Inositol, Cell Line, Tumor, IMP Dehydrogenase, Drug Resistance, Neoplasm, Enzyme Activation, Mice, Inbred C57BL

Published Open-Access

yes

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