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

Oncogene. 2021 Mar;40(9):1690-1705. doi: 10.1038/s41388-021-01658-z.

Chenchu Lin ^# ¹ ², Alicia M Blessing ^# ³ ⁴ ⁵, Thomas L Pulliam ¹ ⁴ ⁵, Yan Shi ⁴, Sandi R Wilkenfeld ¹ ², Jenny J Han ¹, Mollianne M Murray ¹, Alexander H Pham ⁴, Kevin Duong ², Sonja N Brun ⁶, Reuben J Shaw ⁶, Michael M Ittmann ⁷ ⁸ ⁹, Daniel E Frigo ¹⁰ ¹¹ ¹² ¹³ ¹⁴

Affiliations

1 Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
2 The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA.
3 Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
4 Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX, USA.
5 Department of Biology and Biochemistry, University of Houston, Houston, TX, USA.
6 Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA, USA.
7 Departments of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA.
8 Dan L. Duncan Cancer Center, Houston, TX, USA.
9 Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA.
10 Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. [email protected].
11 Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX, USA. [email protected].
12 Department of Biology and Biochemistry, University of Houston, Houston, TX, USA. [email protected].
13 Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. [email protected].
14 The Houston Methodist Research Institute, Houston, TX, USA. [email protected].
# Contributed equally.

PMID: 33531625 DOI: 10.1038/s41388-021-01658-z

Abstract

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 CA²⁺/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.

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