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
Affiliations
Chenchu Lin
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
Thomas L. Pulliam
Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
Jenny J. Han
Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
Jiaqian Xu
Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
Carlos Vera Recio
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Sandi R. Wilkenfeld
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
Yan Shi
Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
Manoj Kushwaha
Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA
Sarah Bench
Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA
Eduardo Ruiz
Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
Sanjanaa Senthilkumar
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
Jayasurya Dileep
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
Peter D.A. Shepherd
Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Nora M. Navone
Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Albert R. Klekers
Department of Abdominal Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Elizabeth M. Whitley
Department of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Michael M. Ittmann
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
Livia S. Eberlin
Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA; Department of Chemistry, The University of Texas at Austin, Austin, TX 78712, USA
Wenyi Wang
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Daniel E. Frigo
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; Corresponding author
Summary: 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.
