Inhibition of CAMKK2 impairs autophagy and castration-resistant prostate cancer via suppression of AMPK-ULK1 signaling

• Published in: Oncogene 2021-03, Vol.40 (9), p.1690-1705
• Main Authors: Lin, Chenchu, Blessing, Alicia M., Pulliam, Thomas L., Shi, Yan, Wilkenfeld, Sandi R., Han, Jenny J., Murray, Mollianne M., Pham, Alexander H., Duong, Kevin, Brun, Sonja N., Shaw, Reuben J., Ittmann, Michael M., Frigo, Daniel E.
• Format: Article
• Language: English
• Subjects: 101/28; 13/109; 13/2; 13/89; 13/95; 14/5; 14/63; 38/35; 45/41; 45/44; 631/67/1059/602; 631/67/589/466; 631/80/39; 64/60; 82/51; 82/80; 96/1; 96/106; AMP; AMP-activated protein kinase; AMP-Activated Protein Kinase Kinases; Androgen receptors; Animal models; Animals; Apoptosis; Autophagy; Autophagy - drug effects; Autophagy-Related Protein-1 Homolog - genetics; Ca2+/calmodulin-dependent protein kinase; Calcium-binding protein; Calcium-Calmodulin-Dependent Protein Kinase Kinase - genetics; Calmodulin; Care and treatment; Castration; Cell Biology; Cell Line, Tumor; Cell Proliferation - drug effects; Cellular signal transduction; Chloroquine; Chloroquine - pharmacology; Clinical trials; Development and progression; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Genetic aspects; Health aspects; Human Genetics; Humans; Internal Medicine; Intracellular Signaling Peptides and Proteins - genetics; Kinases; Male; Medicine; Medicine & Public Health; Mice; Oncology; Phagocytosis; Phosphorylation - drug effects; Prostate - metabolism; Prostate - pathology; Prostate cancer; Prostatic Neoplasms, Castration-Resistant - drug therapy; Prostatic Neoplasms, Castration-Resistant - genetics; Prostatic Neoplasms, Castration-Resistant - pathology; Protein kinases; Protein Kinases - genetics; Rapamycin; Receptors, Androgen - genetics; Signal Transduction - drug effects; TOR protein
• ISSN: 0950-9232; 1476-5594; 1476-5594
• DOI: 10.1038/s41388-021-01658-z

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.