Cholesterol metabolism regulated by CAMKK2-CREB signaling promotes castration-resistant prostate cancer

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

doi:10.1016/j.celrep.2025.115792

Cholesterol metabolism regulated by CAMKK2-CREB signaling promotes castration-resistant prostate cancer

Cell Rep. 2025 Jun 24;44(6):115792. doi: 10.1016/j.celrep.2025.115792. Epub 2025 Jun 7.

Authors

Chenchu Lin¹, Thomas L Pulliam², Jenny J Han², Jiaqian Xu², Carlos Vera Recio³, Sandi R Wilkenfeld⁴, Yan Shi², Manoj Kushwaha⁵, Sarah Bench⁵, Eduardo Ruiz², Sanjanaa Senthilkumar⁶, Jayasurya Dileep⁷, Peter D A Shepherd⁸, Nora M Navone⁸, Albert R Klekers⁹, Elizabeth M Whitley¹⁰, Michael M Ittmann¹¹, Livia S Eberlin¹², Wenyi Wang³, Daniel E Frigo¹³

Affiliations

¹ Department 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.
² Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
³ Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁴ Department 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.
⁵ Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA.
⁶ Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Mayo Clinic Alix School of Medicine, Phoenix, AZ 85054, USA.
⁷ Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; McKetta Department of Chemical Engineering, University of Texas at Austin, Austin, TX 78712, USA.
⁸ Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁹ Department of Abdominal Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹⁰ Department of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹¹ Departments of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Houston, TX 77030, USA; Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX 77030, USA.
¹² Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA; Department of Chemistry, The University of Texas at Austin, Austin, TX 78712, USA.
¹³ Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX 77204, USA; Department of Biology and Biochemistry, University of Houston, Houston, TX 77004, USA. Electronic address: frigo@mdanderson.org.

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: AMPK; CAMKI; CAMKK2; CP: Cancer; CP: Metabolism; CREB; androgen receptor; cholesterol; metabolism; prostate cancer.

MeSH terms

AMP-Activated Protein Kinases / metabolism
Animals
Calcium-Calmodulin-Dependent Protein Kinase Kinase* / genetics
Calcium-Calmodulin-Dependent Protein Kinase Kinase* / metabolism
Cell Line, Tumor
Cell Proliferation
Cholesterol* / metabolism
Cyclic AMP Response Element-Binding Protein* / metabolism
Humans
Male
Mice
Phosphorylation
Prostatic Neoplasms, Castration-Resistant* / genetics
Prostatic Neoplasms, Castration-Resistant* / metabolism
Prostatic Neoplasms, Castration-Resistant* / pathology
Signal Transduction*

Substances

Cyclic AMP Response Element-Binding Protein
Calcium-Calmodulin-Dependent Protein Kinase Kinase
CAMKK2 protein, human
Cholesterol
CREB1 protein, human
AMP-Activated Protein Kinases

Abstract

MeSH terms

Substances

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