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
Affiliations
Joanna L Gillis
Adelaide Medical School, University of Adelaide, Adelaide, Australia; South Australian Health and Medical Research Institute, Adelaide, Australia
Josephine A Hinneh
Adelaide Medical School, University of Adelaide, Adelaide, Australia; South Australian Health and Medical Research Institute, Adelaide, Australia; Department of Urology, Nagoya University Graduate School of Medicine, Nagoya, Japan
Natalie K Ryan
Adelaide Medical School, University of Adelaide, Adelaide, Australia; South Australian Health and Medical Research Institute, Adelaide, Australia
Swati Irani
Adelaide Medical School, University of Adelaide, Adelaide, Australia; South Australian Health and Medical Research Institute, Adelaide, Australia
Max Moldovan
South Australian Health and Medical Research Institute, Adelaide, Australia
Lake-Ee Quek
School of Mathematics and Statistics, Charles Perkins Centre, Faculty of Science, The University of Sydney, Camperdown, Australia
Raj K Shrestha
Adelaide Medical School, University of Adelaide, Adelaide, Australia; Flinders Health and Medical Research Institute, Flinders University, College of Medicine and Public Health, Bedford Park, Australia; Dame Roma Mitchell Cancer Research Laboratories, University of Adelaide, Adelaide, Australia; Freemasons Centre for Male Health and Wellbeing, University of Adelaide, Adelaide, Australia
Adrienne R Hanson
Flinders Health and Medical Research Institute, Flinders University, College of Medicine and Public Health, Bedford Park, Australia
Jianling Xie
Flinders Health and Medical Research Institute, Flinders University, College of Medicine and Public Health, Bedford Park, Australia
School of Medical Sciences and Prince of Wales Clinical School, University of New South Wales, Sydney, Australia
Margaret M Centenera
Adelaide Medical School, University of Adelaide, Adelaide, Australia; South Australian Health and Medical Research Institute, Adelaide, Australia; Freemasons Centre for Male Health and Wellbeing, University of Adelaide, Adelaide, Australia
Ian G Mills
Centre for Cancer Research and Cell Biology, Queen's University Belfast, Northern Ireland, United Kingdom; Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom
David J Lynn
South Australian Health and Medical Research Institute, Adelaide, Australia; Flinders Health and Medical Research Institute, Flinders University, College of Medicine and Public Health, Bedford Park, Australia
Adelaide Medical School, University of Adelaide, Adelaide, Australia; Flinders Health and Medical Research Institute, Flinders University, College of Medicine and Public Health, Bedford Park, Australia; Dame Roma Mitchell Cancer Research Laboratories, University of Adelaide, Adelaide, Australia; Freemasons Centre for Male Health and Wellbeing, University of Adelaide, Adelaide, Australia
Adelaide Medical School, University of Adelaide, Adelaide, Australia; South Australian Health and Medical Research Institute, Adelaide, Australia; Freemasons Centre for Male Health and Wellbeing, University of Adelaide, Adelaide, Australia
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.
