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Updated: Sep 19, 2025

A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
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Cholesterol metabolism regulated by CAMKK2-CREB signaling promotes castration-resistant prostate cancer

Chenchu Lin1, Thomas L Pulliam2, Jenny J Han2

  • 1Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; UTHealth Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center Houston, TX 77030, USA; Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Cell Reports
|June 8, 2025
PubMed

Insights

Castration-resistant prostate cancer (CRPC) growth is driven by CAMKK2 via CAMKI and CREB, not AMPK. Targeting CREB1/ATF1 offers a promising new therapeutic strategy for CRPC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Castration-resistant prostate cancer (CRPC) is an incurable malignancy requiring novel therapeutic targets.
  • CAMKK2 is implicated in prostate cancer, with its role often linked to AMP-activated protein kinase (AMPK).

Purpose of the Study:

  • To investigate alternative downstream pathways of CAMKK2 in promoting prostate cancer growth.
  • To identify and validate a novel CAMKK2-regulated oncogenic pathway for CRPC treatment.

Main Methods:

  • Unbiased transcriptomics to identify CAMKK2-regulated genes.
  • In vitro and in vivo molecular, genetic, and pharmacological validation.
  • Assessment of CAMKK2-CAMKI-CREB signaling axis and its impact on CRPC growth.

Main Results:

  • CAMKK2 promotes CRPC growth via CAMKIα and CREB, independent of AMPK.
  • CREB-mediated transcription is a key CAMKK2-regulated process.
  • Co-targeting redundant CREB family members CREB1 and ATF1 effectively inhibits CRPC growth with minimal side effects.
  • CAMKK2 and CREB enhance CRPC growth by augmenting cholesterol metabolism.

Conclusions:

  • A novel CAMKK2-CAMKI-CREB oncogenic pathway drives CRPC progression.
  • Targeting CREB1 and ATF1 represents a potential therapeutic strategy for CRPC.
  • Modulating cholesterol metabolism is implicated in CAMKK2-driven CRPC growth.
Keywords:
AMPKCAMKICAMKK2CP: CancerCP: MetabolismCREBandrogen receptorcholesterolmetabolismprostate cancer

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