PMID- 33531625 OWN - NLM STAT- MEDLINE DCOM- 20210729 LR - 20231223 IS - 1476-5594 (Electronic) IS - 0950-9232 (Print) IS - 0950-9232 (Linking) VI - 40 IP - 9 DP - 2021 Mar TI - Inhibition of CAMKK2 impairs autophagy and castration-resistant prostate cancer via suppression of AMPK-ULK1 signaling. PG - 1690-1705 LID - 10.1038/s41388-021-01658-z [doi] AB - Previous work has suggested androgen receptor (AR) signaling mediates prostate cancer progression in part through the modulation of autophagy. However, clinical trials testing autophagy inhibition using chloroquine derivatives in men with castration-resistant prostate cancer (CRPC) have yet to yield promising results, potentially due to the side effects of this class of compounds. We hypothesized that identification of the upstream activators of autophagy in prostate cancer could highlight alternative, context-dependent targets for blocking this important cellular process during disease progression. Here, we used molecular, genetic, and pharmacological approaches to elucidate an AR-mediated autophagy cascade involving Ca(2+)/calmodulin-dependent protein kinase kinase 2 (CAMKK2; a kinase with a restricted expression profile), 5'-AMP-activated protein kinase (AMPK), and Unc-51 like autophagy activating kinase 1 (ULK1), but independent of canonical mechanistic target of rapamycin (mTOR) activity. Increased CAMKK2-AMPK-ULK1 signaling correlated with disease progression in genetic mouse models and patient tumor samples. Importantly, CAMKK2 disruption impaired tumor growth and prolonged survival in multiple CRPC preclinical mouse models. Similarly, an inhibitor of AMPK-ULK1 blocked autophagy, cell growth, and colony formation in prostate cancer cells. Collectively, our findings converge to demonstrate that AR can co-opt the CAMKK2-AMPK-ULK1 signaling cascade to promote prostate cancer by increasing autophagy. Thus, this pathway may represent an alternative autophagic target in CRPC. FAU - Lin, Chenchu AU - Lin C AD - Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. AD - The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA. FAU - Blessing, Alicia M AU - Blessing AM AD - Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. AD - Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX, USA. AD - Department of Biology and Biochemistry, University of Houston, Houston, TX, USA. FAU - Pulliam, Thomas L AU - Pulliam TL AD - Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. AD - Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX, USA. AD - Department of Biology and Biochemistry, University of Houston, Houston, TX, USA. FAU - Shi, Yan AU - Shi Y AD - Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX, USA. FAU - Wilkenfeld, Sandi R AU - Wilkenfeld SR AD - Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. AD - The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA. FAU - Han, Jenny J AU - Han JJ AD - Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. FAU - Murray, Mollianne M AU - Murray MM AD - Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. FAU - Pham, Alexander H AU - Pham AH AD - Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX, USA. FAU - Duong, Kevin AU - Duong K AD - The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA. FAU - Brun, Sonja N AU - Brun SN AD - Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA, USA. FAU - Shaw, Reuben J AU - Shaw RJ AD - Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA, USA. FAU - Ittmann, Michael M AU - Ittmann MM AUID- ORCID: 0000-0003-4802-0978 AD - Departments of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA. AD - Dan L. Duncan Cancer Center, Houston, TX, USA. AD - Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA. FAU - Frigo, Daniel E AU - Frigo DE AUID- ORCID: 0000-0002-0713-471X AD - Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. frigo@mdanderson.org. AD - Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX, USA. frigo@mdanderson.org. AD - Department of Biology and Biochemistry, University of Houston, Houston, TX, USA. frigo@mdanderson.org. AD - Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. frigo@mdanderson.org. AD - The Houston Methodist Research Institute, Houston, TX, USA. frigo@mdanderson.org. LA - eng GR - P30 CA016672/CA/NCI NIH HHS/United States GR - P50 CA140388/CA/NCI NIH HHS/United States GR - R01 CA184208/CA/NCI NIH HHS/United States GR - R35 CA220538/CA/NCI NIH HHS/United States GR - P30 CA014195/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20210202 PL - England TA - Oncogene JT - Oncogene JID - 8711562 RN - 0 (AR protein, human) RN - 0 (Intracellular Signaling Peptides and Proteins) RN - 0 (Receptors, Androgen) RN - 886U3H6UFF (Chloroquine) RN - EC 2.7.- (Protein Kinases) RN - EC 2.7.11.1 (Autophagy-Related Protein-1 Homolog) RN - EC 2.7.11.1 (ULK1 protein, human) RN - EC 2.7.11.17 (CAMKK2 protein, human) RN - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Kinase) RN - EC 2.7.11.3 (AMP-Activated Protein Kinase Kinases) SB - IM MH - AMP-Activated Protein Kinase Kinases MH - Animals MH - Autophagy/drug effects MH - Autophagy-Related Protein-1 Homolog/*genetics MH - Calcium-Calmodulin-Dependent Protein Kinase Kinase/*genetics MH - Cell Line, Tumor MH - Cell Proliferation/drug effects MH - Chloroquine/pharmacology MH - Gene Expression Regulation, Neoplastic/drug effects MH - Humans MH - Intracellular Signaling Peptides and Proteins/*genetics MH - Male MH - Mice MH - Phosphorylation/drug effects MH - Prostate/metabolism/pathology MH - Prostatic Neoplasms, Castration-Resistant/*drug therapy/genetics/pathology MH - Protein Kinases/*genetics MH - Receptors, Androgen/*genetics MH - Signal Transduction/drug effects PMC - PMC7935762 MID - NIHMS1663386 EDAT- 2021/02/04 06:00 MHDA- 2021/07/30 06:00 PMCR- 2021/08/02 CRDT- 2021/02/03 05:54 PHST- 2020/06/26 00:00 [received] PHST- 2021/01/14 00:00 [accepted] PHST- 2020/12/18 00:00 [revised] PHST- 2021/02/04 06:00 [pubmed] PHST- 2021/07/30 06:00 [medline] PHST- 2021/02/03 05:54 [entrez] PHST- 2021/08/02 00:00 [pmc-release] AID - 10.1038/s41388-021-01658-z [pii] AID - 10.1038/s41388-021-01658-z [doi] PST - ppublish SO - Oncogene. 2021 Mar;40(9):1690-1705. doi: 10.1038/s41388-021-01658-z. Epub 2021 Feb 2.