A feedback loop between the androgen receptor and 6-phosphogluoconate dehydrogenase (6PGD) drives prostate cancer growth
- University of Adelaide, Australia
- South Australian Health and Medical Research Institute, Australia
- University of Sydney, Australia
- Flinders University, Australia
- University of New South Wales, Australia
- 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
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The Cancer Genome Atlas Prostate Adenocarcinoma (TCGA-PRAD)National Cancer Institute, TCGA-PRAD.
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Androgen receptor programming in human tissue implicates HOXB13 in prostate pathogenesis [ChIP-Seq]NCBI The Gene Expression Omnibus, GSE56288 (GSM1358397).
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Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer [ChIP-Seq]NCBI The Gene Expression Omnibus, GSE56288 (GSM1328950).
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Overexpression of c-Myc antagonises transcriptional output of the androgen receptor in prostate cancer [ChIP-Seq]NCBI The Gene Expression Omnibus, GSE73994 (GSM1907200).
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SREBF1 ChIP-seq on human MCF-7NCBI The Gene Expression Omnibus, GSE91561 (ENCFF911YFI).
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SREBF1 ChIP-seq on human HepG2 treated with insulinNCBI The Gene Expression Omnibus, GSE31477 (GSM935627; ENCFF000XXR).
Article and author information
Author details
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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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
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