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
-
The Cancer Genome Atlas Prostate Adenocarcinoma (TCGA-PRAD)National Cancer Institute, TCGA-PRAD.
-
Androgen receptor programming in human tissue implicates HOXB13 in prostate pathogenesis [ChIP-Seq]NCBI The Gene Expression Omnibus, GSE56288 (GSM1358397).
-
Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer [ChIP-Seq]NCBI The Gene Expression Omnibus, GSE56288 (GSM1328950).
-
Overexpression of c-Myc antagonises transcriptional output of the androgen receptor in prostate cancer [ChIP-Seq]NCBI The Gene Expression Omnibus, GSE73994 (GSM1907200).
-
SREBF1 ChIP-seq on human MCF-7NCBI The Gene Expression Omnibus, GSE91561 (ENCFF911YFI).
-
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.
Metrics
-
- 2,571
- views
-
- 349
- downloads
-
- 24
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
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
Further reading
-
- Cancer Biology
Most human pancreatic ductal adenocarcinoma (PDAC) are not infiltrated with cytotoxic T cells and are highly resistant to immunotherapy. Over 90% of PDAC have oncogenic KRAS mutations, and phosphoinositide 3-kinases (PI3Ks) are direct effectors of KRAS. Our previous study demonstrated that ablation of Pik3ca in KPC (KrasG12D; Trp53R172H; Pdx1-Cre) pancreatic cancer cells induced host T cells to infiltrate and completely eliminate the tumors in a syngeneic orthotopic implantation mouse model. Now, we show that implantation of Pik3ca−/− KPC (named αKO) cancer cells induces clonal enrichment of cytotoxic T cells infiltrating the pancreatic tumors. To identify potential molecules that can regulate the activity of these anti-tumor T cells, we conducted an in vivo genome-wide gene-deletion screen using αKO cells implanted in the mouse pancreas. The result shows that deletion of propionyl-CoA carboxylase subunit B gene (Pccb) in αKO cells (named p-αKO) leads to immune evasion, tumor progression, and death of host mice. Surprisingly, p-αKO tumors are still infiltrated with clonally enriched CD8+ T cells but they are inactive against tumor cells. However, blockade of PD-L1/PD1 interaction reactivated these clonally enriched T cells infiltrating p-αKO tumors, leading to slower tumor progression and improve survival of host mice. These results indicate that Pccb can modulate the activity of cytotoxic T cells infiltrating some pancreatic cancers and this understanding may lead to improvement in immunotherapy for this difficult-to-treat cancer.
-
- Cancer Biology
- Immunology and Inflammation
In this study, we present a proof-of-concept classical vaccination experiment that validates the in silico identification of tumor neoantigens (TNAs) using a machine learning-based platform called NAP-CNB. Unlike other TNA predictors, NAP-CNB leverages RNA-seq data to consider the relative expression of neoantigens in tumors. Our experiments show the efficacy of NAP-CNB. Predicted TNAs elicited potent antitumor responses in mice following classical vaccination protocols. Notably, optimal antitumor activity was observed when targeting the antigen with higher expression in the tumor, which was not the most immunogenic. Additionally, the vaccination combining different neoantigens resulted in vastly improved responses compared to each one individually, showing the worth of multiantigen-based approaches. These findings validate NAP-CNB as an innovative TNA identification platform and make a substantial contribution to advancing the next generation of personalized immunotherapies.
