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

Joanna L Gillis; Josephine A Hinneh; Natalie K Ryan; Swati Irani; Max Moldovan; Lake-Ee Quek; Raj K Shrestha; Adrienne R Hanson; Jianling Xie; Andrew J Hoy; Jeff Holst; Margaret M Centenera; Ian G Mills; David J Lynn; Luke A Selth; Lisa M Butler

doi:10.7554/eLife.62592

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

Elife. 2021 Aug 12:10:e62592. doi: 10.7554/eLife.62592.

Authors

Joanna L Gillis^{1

2}, Josephine A Hinneh^{1

2

3}, Natalie K Ryan^{1

2}, Swati Irani^{1

2}, Max Moldovan², Lake-Ee Quek⁴, Raj K Shrestha^{1

5

6

7}, Adrienne R Hanson⁵, Jianling Xie⁵, Andrew J Hoy⁸, Jeff Holst⁹, Margaret M Centenera^{1

2

7}, Ian G Mills^{10

11}, David J Lynn^{2

5}, Luke A Selth^{1

5

6

7}, Lisa M Butler^{1

2

7}

Affiliations

¹ Adelaide Medical School, University of Adelaide, Adelaide, Australia.
² South Australian Health and Medical Research Institute, Adelaide, Australia.
³ Department of Urology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
⁴ School of Mathematics and Statistics, Charles Perkins Centre, Faculty of Science, The University of Sydney, Camperdown, Australia.
⁵ Flinders Health and Medical Research Institute, Flinders University, College of Medicine and Public Health, Bedford Park, Australia.
⁶ Dame Roma Mitchell Cancer Research Laboratories, University of Adelaide, Adelaide, Australia.
⁷ Freemasons Centre for Male Health and Wellbeing, University of Adelaide, Adelaide, Australia.
⁸ School of Medical Sciences, Charles Perkins Centre, Faculty of Medicine and Health, The University of Sydney, Camperdown, Australia.
⁹ School of Medical Sciences and Prince of Wales Clinical School, University of New South Wales, Sydney, Australia.
¹⁰ Centre for Cancer Research and Cell Biology, Queen's University Belfast, Northern Ireland, United Kingdom.
¹¹ Nuffield Department of Surgical Sciences, University of Oxford, Oxford, 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 acetyl-CoA carboxylase 1 (ACC1) and mammalian target of rapamycin complex 1 (mTORC1); 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 6PGD, 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.

Keywords: androgen receptor; cancer biology; human; pentose phosphate pathway; prostate cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

AMP-Activated Protein Kinases / metabolism
Acetyl-CoA Carboxylase / metabolism
Cell Line
Emodin / analogs & derivatives
Feedback
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques
Glyceraldehyde-3-Phosphate Dehydrogenases / metabolism*
Humans
Male
Mechanistic Target of Rapamycin Complex 1 / metabolism
Pentose Phosphate Pathway
Prostatic Neoplasms / genetics
Prostatic Neoplasms / metabolism*
Receptors, Androgen / metabolism*
Signal Transduction
Sterol Regulatory Element Binding Protein 1 / metabolism

Substances

AR protein, human
Receptors, Androgen
SREBF1 protein, human
Sterol Regulatory Element Binding Protein 1
Glyceraldehyde-3-Phosphate Dehydrogenases
Mechanistic Target of Rapamycin Complex 1
AMP-Activated Protein Kinases
ACACA protein, human
Acetyl-CoA Carboxylase
physcione
Emodin

Associated data

GEO/GSE152254
GEO/GSE48403
GEO/GSE56288(GSM1358397)
GEO/GSE56288(GSM1328950)
GEO/GSE73994(GSM1907200)
GEO/GSE91561(ENCFF911YFI)
GEO/GSE31477(GSM935627;ENCFF000XXR)

Grants and funding

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