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

Oncogene volume 40, pages 1690–1705 (2021)Cite this article

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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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Fig. 1: Chloroquine inhibits castration-resistant prostate cancer (CRPC) growth in vivo.
Fig. 2: CAMKK2 increases autophagy in prostate cancer cells.
Fig. 3: CAMKK2 promotes autophagic flux.
Fig. 4: CAMKK2 is required for CRPC tumor growth in vivo.
Fig. 5: AR-CAMKK2-AMPK signaling increases autophagy by phosphorylating ULK1 at serine 555.
Fig. 6: High ULK1 tumor expression predicts poor patient prognosis in independent clinical cohorts of men with prostate cancer.
Fig. 7: The ULK1 inhibitor SBI-0206965 represses prostate cancer cell growth.
Fig. 8: Working model depicting how AR-CAMKK2-AMPK signaling regulates autophagy by ULK1 phosphorylation and activation in prostate cancer.

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Acknowledgements

We thank Drs. Mondira Kundu, Christopher Counter and Nancy Weigel for plasmids and reagents, Kenneth Dunner, Jr. in the High Resolution Electron Microscopy Core Facility at MDACC for help with TEM, and Dr. Jeff Spencer for help with sgRNA design. This work was supported by grants from the National Institutes of Health (NIH R01CA184208 to DEF), American Cancer Society (RSG-16-084-01-TBE to DEF), an Institutional Research Grant (to DEF) and generous philanthropic contributions to The University of Texas MD Anderson Moon Shots Program (to DEF). This work was also supported by an Antje Wuelfrath Gee and Harry Gee, Jr. Family Legacy Scholarship, Robert Hazelwood Graduate Fellowship for Cancer Research (to CL) and MD Anderson Odyssey fellow supported by the CFP foundation (to AMB). Electron microscopy was performed by the CCSG-funded MDACC High Resolution Electron Microscopy Facility while histology was performed with the CCSG-funded MDACC Research Histology Core Laboratory, NIH grant P30CA016672.

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  1. These authors contributed equally: Chenchu Lin, Alicia M. Blessing

Authors and Affiliations

  1. Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Chenchu Lin, Thomas L. Pulliam, Sandi R. Wilkenfeld, Jenny J. Han, Mollianne M. Murray & Daniel E. Frigo

  2. The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA

    Chenchu Lin, Sandi R. Wilkenfeld & Kevin Duong

  3. Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Alicia M. Blessing

  4. Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX, USA

    Alicia M. Blessing, Thomas L. Pulliam, Yan Shi, Alexander H. Pham & Daniel E. Frigo

  5. Department of Biology and Biochemistry, University of Houston, Houston, TX, USA

    Alicia M. Blessing, Thomas L. Pulliam & Daniel E. Frigo

  6. Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA, USA

    Sonja N. Brun & Reuben J. Shaw

  7. Departments of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA

    Michael M. Ittmann

  8. Dan L. Duncan Cancer Center, Houston, TX, USA

    Michael M. Ittmann

  9. Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA

    Michael M. Ittmann

  10. Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Daniel E. Frigo

  11. The Houston Methodist Research Institute, Houston, TX, USA

    Daniel E. Frigo

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DEF has received research funding from GTx, Inc and has a familial relationship with Hummingbird Bioscience, MAIA Biotechnology, Alms Therapeutics, Hinova Pharmaceuticals and Barricade Therapeutics. AMB is currently employed by and has stock in Clovis Oncology. The other authors report no potential conflicts of interest.

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Lin, C., Blessing, A.M., Pulliam, T.L. et al. Inhibition of CAMKK2 impairs autophagy and castration-resistant prostate cancer via suppression of AMPK-ULK1 signaling. Oncogene 40, 1690–1705 (2021). https://doi.org/10.1038/s41388-021-01658-z

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