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Updated: Jun 9, 2025

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

Che-Chia Hsu1,2, Guihua Wang2, Chien-Feng Li3

  • 1Department of Pathology, Duke University Medical Center, Duke University School of Medicine, Durham, NC, USA.

The Journal of Experimental Medicine
|October 29, 2024
PubMed

Insights

Inositol, produced by IMPA1, fuels prostate cancer stem cells (PCSCs) and drives resistance to androgen ablation therapy (ABT). Targeting the IMPA1/inositol/IMPDH2 pathway halts castration-resistant prostate cancer (CRPC) progression.

Area of Science:

  • Metabolomics
  • Cancer Biology
  • Molecular Oncology

Background:

  • Prostate cancer stem cells (PCSCs) drive castration-resistant prostate cancer (CRPC) and resistance to androgen ablation therapy (ABT).
  • The specific metabolites regulating PCSC maintenance and CRPC progression remain largely unknown.

Purpose of the Study:

  • To identify key metabolites involved in PCSC maintenance during ABT.
  • To elucidate the role of inositol and its metabolic pathway in CRPC progression and ABT resistance.

Main Methods:

  • Conditional Impa1 knockout in mouse prostate.
  • Analysis of PCSC pool and properties.
  • In vivo studies using TRAMP mice, CRPC xenografts, and patient-derived xenograft (PDX) models.
  • Genetic and pharmacological targeting of the IMPA1/inositol/IMPDH2 axis.

Main Results:

  • IMPA1-derived inositol is enriched in PCSCs and crucial for their maintenance and CRPC progression.
  • Conditional Impa1 knockout reduced PCSCs, halted CRPC, and prolonged survival in TRAMP mice.
  • Inositol activates IMPDH2, synthesizing guanylate nucleotides essential for ARlow/- PCSCs, driving CRPC and ABT resistance.
  • The IMPA1/inositol/IMPDH2 axis is upregulated in human prostate cancer, correlating with poor survival.
  • Targeting this axis abrogated CRPC and overcame ABT resistance in preclinical models.

Conclusions:

  • IMPDH2 acts as an inositol sensor, and its activation by inositol is a key mechanism maintaining PCSCs for CRPC and ABT resistance.
  • The IMPA1/inositol/IMPDH2 pathway represents a promising therapeutic target for overcoming CRPC and ABT resistance.

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