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Androgens regulate prostate cancer cell growth via an AMPK-PGC-1α-mediated metabolic switch

Oncogene volume 33, pages 5251–5261 (2014)Cite this article

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Abstract

Prostate cancer is the most commonly diagnosed malignancy among men in industrialized countries, accounting for the second leading cause of cancer-related deaths. Although we now know that the androgen receptor (AR) is important for progression to the deadly advanced stages of the disease, it is poorly understood what AR-regulated processes drive this pathology. Here we demonstrate that AR regulates prostate cancer cell growth via the metabolic sensor 5′-AMP-activated protein kinase (AMPK), a kinase that classically regulates cellular energy homeostasis. In patients, activation of AMPK correlated with prostate cancer progression. Using a combination of radiolabeled assays and emerging metabolomic approaches, we also show that prostate cancer cells respond to androgen treatment by increasing not only rates of glycolysis, as is commonly seen in many cancers, but also glucose and fatty acid oxidation. Importantly, this effect was dependent on androgen-mediated AMPK activity. Our results further indicate that the AMPK-mediated metabolic changes increased intracellular ATP levels and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α)-mediated mitochondrial biogenesis, affording distinct growth advantages to the prostate cancer cells. Correspondingly, we used outlier analysis to determine that PGC-1α is overexpressed in a subpopulation of clinical cancer samples. This was in contrast to what was observed in immortalized benign human prostate cells and a testosterone-induced rat model of benign prostatic hyperplasia. Taken together, our findings converge to demonstrate that androgens can co-opt the AMPK-PGC-1α signaling cascade, a known homeostatic mechanism, to increase prostate cancer cell growth. The current study points to the potential utility of developing metabolic-targeted therapies directed toward the AMPK-PGC-1α signaling axis for the treatment of prostate cancer.

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Acknowledgements

We thank members of the Frigo Laboratory for technical advice, helpful suggestions and critical comments on this study and manuscript. We also thank Paul Landry for his assistance with Amira and mitochondrial volume measurements, the Duke University Department of Pathology’s Electron Microscopy Core for help with transmission electron microscopy; Drs Dean Tang, Geoffrey Girnun and Thomas Westbrook for generously providing the LAPC9-derived tumors, shPGC-1α constructs and pINDUCER22, respectively; Drs Timothy Koves and Pradip Saha for their advice on the CO2 trap assays; Dr Christopher Newgard for help with the metabolomics; and Drs Sean McGuire and Kevin Phillips for critically reading this manuscript. This work was supported by NIH grants K01DK084205 (DEF), P30EY007551 (ARB), R00CA125937 (LX), P30CA125123 (Dan L Duncan Cancer Center Human Tissue Acquisition and Pathology Core), DoD/PCRP grant W81XWH-12-1-0204 (DEF), CPRIT grant RP110005 (LX) and grants from the Texas Emerging Technology Fund, the Golfers Against Cancer (DEF), the Urology Care Foundation Research Scholars Program and AUA Southeastern Section (FGR).

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Authors and Affiliations

  1. Department of Biology and Biochemistry, Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX, USA

    J B Tennakoon, Y Shi, J J Han, E Tsouko, M A White & D E Frigo

  2. College of Optometry, University of Houston, Houston, TX, USA

    A R Burns

  3. Center for Genomic Medicine, Houston Methodist Research Institute, Houston, TX, USA

    A Zhang, X Xia & D E Frigo

  4. Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA

    O R Ilkayeva

  5. Departments of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA

    L Xin

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

    L Xin & M M Ittmann

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

    L Xin & M M Ittmann

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

    M M Ittmann

  9. Veterans Affairs Medical Center and South Florida VA Foundation for Research and Education, Miami, FL, USA

    F G Rick & A V Schally

  10. Department of Urology, Florida International University, Herbert Wertheim College of Medicine, Miami, FL, USA

    F G Rick

  11. Department of Pathology, University of Miami, Miller School of Medicine, Miami, FL, USA

    A V Schally

  12. Divisions of Hematology/Oncology, University of Miami, Miller School of Medicine, Miami, FL, USA

    A V Schally

  13. Division of Endocrinology, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL, USA

    A V Schally

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Tennakoon, J., Shi, Y., Han, J. et al. Androgens regulate prostate cancer cell growth via an AMPK-PGC-1α-mediated metabolic switch. Oncogene 33, 5251–5261 (2014). https://doi.org/10.1038/onc.2013.463

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