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

Abstract
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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

1. Gillis JL
2. Hinneh JA
3. Ryan NK
4. Irani S
5. Moldovan M
6. Quek LE
7. Hoy AJ
8. Holst J
9. Centenera MM
10. Mills IG
11. Lynn DJ
12. Selth LA
13. Butler LM
(2020) A feedback loop between the androgen receptor and 6-phosphogluoconate dehydrogenase (6PGD) drives prostate cancer growth
NCBI Gene Expression Omnibus, GSE152254.

http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE152254

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https://www.nature.com/articles/s41467-018-03573-6#Sec31

Article and author information

Author details

Joanna L Gillis

Medicine, University of Adelaide, Adelaide, Australia

Competing interests
The authors declare that no competing interests exist.
Josephine A Hinneh

Medicine, University of Adelaide, Adelaide, Australia

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The authors declare that no competing interests exist.
Natalie K Ryan

Medicine, University of Adelaide, Adelaide, Australia

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The authors declare that no competing interests exist.
Swati Irani

Medicine, University of Adelaide, Adelaide, Australia

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The authors declare that no competing interests exist.
Max Moldovan

Precision Medicine, South Australian Health and Medical Research Institute, Adelaide, Australia

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The authors declare that no competing interests exist.
Lake-Ee Quek

Charles Perkins Centre, University of Sydney, Sydney, Australia

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The authors declare that no competing interests exist.
Raj K Shrestha

Medicine, University of Adelaide, Adelaide, Australia

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The authors declare that no competing interests exist.
Adrienne R Hanson

Flinders University, Bedford Park, Australia

Competing interests
The authors declare that no competing interests exist.
Jianling Xie

Flinders University, Bedford Park, Australia

Competing interests
The authors declare that no competing interests exist.
Andrew J Hoy

Charles Perkins Centre, University of Sydney, Sydney, Australia

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The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-3922-1137
Jeff Holst

School of Medical Sciences, University of New South Wales, Sydney, Australia

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The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-0377-9318
Margaret M Centenera

Medicine, University of Adelaide, Adelaide, Australia

Competing interests
The authors declare that no competing interests exist.
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.
David J Lynn

Precision Medicine, South Australian Health and Medical Research Institute, Adelaide, Australia

Competing interests
The authors declare that no competing interests exist.
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.
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.

"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

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.