Cholesterol Metabolism Regulated by CAMKK2-Creb Signaling Promotes Castration-Resistant Prostate Cancer

Authors

Chenchu Lin
Thomas L Pulliam
Jenny J Han
Jiaqian Xu
Carlos Vera Recio
Sandi R Wilkenfeld
Yan Shi
Manoj Kushwaha
Sarah Bench
Eduardo Ruiz
Sanjanaa Senthilkumar
Jayasurya Dileep
Peter D A Shepherd
Nora M Navone
Albert R Klekers
Elizabeth M Whitley
Michael M Ittmann
Livia S Eberlin
Wenyi Wang
Daniel E Frigo

Publication Date

6-24-2025

Journal

Cell Reports

DOI

10.1016/j.celrep.2025.115792

PMID

40483692

PMCID

PMC12289408

PubMedCentral® Posted Date

7-27-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

Castration-resistant prostate cancer (CRPC) remains an incurable disease in need of improved treatments. CAMKK2 is an emerging therapeutic target whose oncogenic effects in prostate cancer have, to date, been largely attributed to its activation of AMP-activated protein kinase (AMPK). Here, we demonstrate that CAMKK2 promotes prostate cancer growth through an alternative downstream pathway involving CAMKI and CREB. Unbiased transcriptomics identify CREB-mediated transcription as a CAMKK2-regulated process, findings that we validate using diverse molecular, genetic, and pharmacological approaches in vitro and in vivo. CAMKK2 promotes CREB phosphorylation/activation through CAMKIα independently of AMPK, CAMKIV, or other CAMKI isoforms. Functionally, the CREB family members CREB1 and ATF1 exhibit close redundancy, necessitating co-targeting for optimal anti-tumor efficacy. An inhibitor of CREB1/ATF1 blocks CRPC with minimal side effects. Mechanistically, CAMKK2 and CREB increase CRPC growth through augmenting cholesterol metabolism. Together, these findings identify an oncogenic pathway that could be exploited for the treatment of CRPC.

Keywords

Male, Humans, Cyclic AMP Response Element-Binding Protein, Prostatic Neoplasms, Castration-Resistant, Calcium-Calmodulin-Dependent Protein Kinase Kinase, Signal Transduction, Animals, Cholesterol, Mice, Cell Line, Tumor, Cell Proliferation, Phosphorylation, AMP-Activated Protein Kinases, AMPK. CAMKI. CAMKK2. CP: Cancer. CP: Metabolism. CREB. androgen receptor. cholesterol. metabolism. prostate cancer

Published Open-Access

yes

Recommended Citation

Lin, Chenchu; Pulliam, Thomas L; Han, Jenny J; et al., "Cholesterol Metabolism Regulated by CAMKK2-Creb Signaling Promotes Castration-Resistant Prostate Cancer" (2025). Faculty, Staff and Student Publications. 4382.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/4382