A feedback loop between the androgen receptor and 6-phosphogluoconate dehydrogenase (6PGD) drives prostate cancer growth

  1. Joanna L Gillis
  2. Josephine A Hinneh
  3. Natalie K Ryan
  4. Swati Irani
  5. Max Moldovan
  6. Lake-Ee Quek
  7. Raj K Shrestha
  8. Adrienne R Hanson
  9. Jianling Xie
  10. Andrew J Hoy
  11. Jeff Holst
  12. Margaret M Centenera
  13. Ian G Mills
  14. David J Lynn
  15. Luke A Selth  Is a corresponding author
  16. Lisa M Butler  Is a corresponding author
  1. University of Adelaide, Australia
  2. South Australian Health and Medical Research Institute, Australia
  3. University of Sydney, Australia
  4. Flinders University, Australia
  5. University of New South Wales, Australia
  6. Queen's University Belfast, United Kingdom

Abstract

Alterations to the androgen receptor (AR) signalling axis and cellular metabolism are hallmarks of prostate cancer. This study provides insight into both hallmarks by uncovering a novel link between AR and the pentose phosphate pathway (PPP). Specifically, we identify 6-phosphogluoconate dehydrogenase (6PGD) as an androgen-regulated gene that is upregulated in prostate cancer. AR increased the expression of 6PGD indirectly via activation of sterol regulatory element binding protein 1 (SREBP1). Accordingly, loss of 6PGD, AR or SREBP1 resulted in suppression of PPP activity, as revealed by 1,2-13C2 glucose metabolic flux analysis. Knockdown of 6PGD also impaired growth and elicited death of prostate cancer cells, at least in part due to increased oxidative stress. We investigated the therapeutic potential of targeting 6PGD using two specific inhibitors, physcion and S3, and observed substantial anti-cancer activity in multiple models of prostate cancer, including aggressive, therapy-resistant models of castration-resistant disease as well as prospectively-collected patient-derived tumour explants. Targeting of 6PGD was associated with two important tumour-suppressive mechanisms: first, increased activity of the AMP-activated protein kinase (AMPK), which repressed anabolic growth-promoting pathways regulated by ACC1 and mTOR; and second, enhanced AR ubiquitylation, associated with a reduction in AR protein levels and activity. Supporting the biological relevance of positive feedback between AR and PGD, pharmacological co-targeting of both factors was more effective in suppressing the growth of prostate cancer cells than single agent therapies. Collectively, this work provides new insight into the dysregulated metabolism of prostate cancer and provides impetus for further investigation of co-targeting AR and the PPP as a novel therapeutic strategy.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figure 1.Sequencing data have been deposited in GEO under accession code GSE152254

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Joanna L Gillis

    Medicine, University of Adelaide, Adelaide, Australia
    Competing interests
    The authors declare that no competing interests exist.
  2. Josephine A Hinneh

    Medicine, University of Adelaide, Adelaide, Australia
    Competing interests
    The authors declare that no competing interests exist.
  3. Natalie K Ryan

    Medicine, University of Adelaide, Adelaide, Australia
    Competing interests
    The authors declare that no competing interests exist.
  4. Swati Irani

    Medicine, University of Adelaide, Adelaide, Australia
    Competing interests
    The authors declare that no competing interests exist.
  5. Max Moldovan

    Precision Medicine, South Australian Health and Medical Research Institute, Adelaide, Australia
    Competing interests
    The authors declare that no competing interests exist.
  6. Lake-Ee Quek

    Charles Perkins Centre, University of Sydney, Sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.
  7. Raj K Shrestha

    Medicine, University of Adelaide, Adelaide, Australia
    Competing interests
    The authors declare that no competing interests exist.
  8. Adrienne R Hanson

    Flinders University, Bedford Park, Australia
    Competing interests
    The authors declare that no competing interests exist.
  9. Jianling Xie

    Flinders University, Bedford Park, Australia
    Competing interests
    The authors declare that no competing interests exist.
  10. Andrew J Hoy

    Charles Perkins Centre, University of Sydney, Sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3922-1137
  11. Jeff Holst

    School of Medical Sciences, University of New South Wales, Sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0377-9318
  12. Margaret M Centenera

    Medicine, University of Adelaide, Adelaide, Australia
    Competing interests
    The authors declare that no competing interests exist.
  13. Ian G Mills

    Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  14. David J Lynn

    Precision Medicine, South Australian Health and Medical Research Institute, Adelaide, Australia
    Competing interests
    The authors declare that no competing interests exist.
  15. Luke A Selth

    Flinders University, Bedford Park, Australia
    For correspondence
    luke.selth@flinders.edu.au
    Competing interests
    The authors declare that no competing interests exist.
  16. Lisa M Butler

    Medicine, University of Adelaide, Adelaide, Australia
    For correspondence
    lisa.butler@adelaide.edu.au
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2698-3220

Funding

Cancer Australia (1138766)

  • Margaret M Centenera
  • Ian G Mills
  • David J Lynn
  • Lisa M Butler

Movember Foundation (MRTA3)

  • Andrew J Hoy
  • Margaret M Centenera
  • Luke A Selth
  • Lisa M Butler

Prostate Cancer Foundation of Australia (MRTA3)

  • Andrew J Hoy
  • Margaret M Centenera
  • Luke A Selth
  • Lisa M Butler

Cancer Council South Australia (Principal Cancer Research Fellowships)

  • Luke A Selth
  • Lisa M Butler

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: Prostate cancer tissue was obtained with informed written consent through the Australian Prostate Cancer BioResource from men undergoing radical prostatectomy at St Andrew's Hospital (Adelaide, Australia). Ethical approval for the use of human prostate tumours was obtained from the Ethics Committees of the University of Adelaide (Adelaide, Australia) and St Andrew's Hospital (Adelaide, Australia). All experiments were performed in accordance with the guidelines of the National Health and Medical Research Council (Australia).

Copyright

© 2021, Gillis et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Joanna L Gillis
  2. Josephine A Hinneh
  3. Natalie K Ryan
  4. Swati Irani
  5. Max Moldovan
  6. Lake-Ee Quek
  7. Raj K Shrestha
  8. Adrienne R Hanson
  9. Jianling Xie
  10. Andrew J Hoy
  11. Jeff Holst
  12. Margaret M Centenera
  13. Ian G Mills
  14. David J Lynn
  15. Luke A Selth
  16. Lisa M Butler
(2021)
A feedback loop between the androgen receptor and 6-phosphogluoconate dehydrogenase (6PGD) drives prostate cancer growth
eLife 10:e62592.
https://doi.org/10.7554/eLife.62592

Share this article

https://doi.org/10.7554/eLife.62592

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