A feedback loop between the androgen receptor and 6-phosphogluoconate dehydrogenase (6PGD) drives prostate cancer growth
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 dehydrogena...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2021-08-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/62592 |
| _version_ | 1797693150233362432 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Joanna L Gillis |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T02:39:25Z |
| format | Article |
| id | doaj.art-7b041890c6d2431cb95c6683b6ee5211 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-03-12T02:39:25Z |
| publishDate | 2021-08-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-7b041890c6d2431cb95c6683b6ee52112023-09-04T09:10:29ZengeLife Sciences Publications LtdeLife2050-084X2021-08-011010.7554/eLife.62592A feedback loop between the androgen receptor and 6-phosphogluoconate dehydrogenase (6PGD) drives prostate cancer growthJoanna L Gillis0Josephine A Hinneh1Natalie K Ryan2Swati Irani3Max Moldovan4Lake-Ee Quek5Raj K Shrestha6Adrienne R Hanson7Jianling Xie8Andrew J Hoy9https://orcid.org/0000-0003-3922-1137Jeff Holst10https://orcid.org/0000-0002-0377-9318Margaret M Centenera11Ian G Mills12David J Lynn13Luke A Selth14https://orcid.org/0000-0002-4686-1418Lisa M Butler15https://orcid.org/0000-0003-2698-3220Adelaide Medical School, University of Adelaide, Adelaide, Australia; South Australian Health and Medical Research Institute, Adelaide, AustraliaAdelaide 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, JapanAdelaide Medical School, University of Adelaide, Adelaide, Australia; South Australian Health and Medical Research Institute, Adelaide, AustraliaAdelaide Medical School, University of Adelaide, Adelaide, Australia; South Australian Health and Medical Research Institute, Adelaide, AustraliaSouth Australian Health and Medical Research Institute, Adelaide, AustraliaSchool of Mathematics and Statistics, Charles Perkins Centre, Faculty of Science, The University of Sydney, Camperdown, AustraliaAdelaide 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, AustraliaFlinders Health and Medical Research Institute, Flinders University, College of Medicine and Public Health, Bedford Park, AustraliaFlinders Health and Medical Research Institute, Flinders University, College of Medicine and Public Health, Bedford Park, AustraliaSchool of Medical Sciences, Charles Perkins Centre, Faculty of Medicine and Health, The University of Sydney, Camperdown, AustraliaSchool of Medical Sciences and Prince of Wales Clinical School, University of New South Wales, Sydney, AustraliaAdelaide 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, AustraliaCentre for Cancer Research and Cell Biology, Queen's University Belfast, Northern Ireland, United Kingdom; Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United KingdomSouth Australian Health and Medical Research Institute, Adelaide, Australia; Flinders Health and Medical Research Institute, Flinders University, College of Medicine and Public Health, Bedford Park, AustraliaAdelaide 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, AustraliaAdelaide 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, AustraliaAlterations 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.https://elifesciences.org/articles/62592pentose phosphate pathwayprostate cancerandrogen receptor |
| spellingShingle | 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 A feedback loop between the androgen receptor and 6-phosphogluoconate dehydrogenase (6PGD) drives prostate cancer growth eLife pentose phosphate pathway prostate cancer androgen receptor |
| title | A feedback loop between the androgen receptor and 6-phosphogluoconate dehydrogenase (6PGD) drives prostate cancer growth |
| title_full | A feedback loop between the androgen receptor and 6-phosphogluoconate dehydrogenase (6PGD) drives prostate cancer growth |
| title_fullStr | A feedback loop between the androgen receptor and 6-phosphogluoconate dehydrogenase (6PGD) drives prostate cancer growth |
| title_full_unstemmed | A feedback loop between the androgen receptor and 6-phosphogluoconate dehydrogenase (6PGD) drives prostate cancer growth |
| title_short | A feedback loop between the androgen receptor and 6-phosphogluoconate dehydrogenase (6PGD) drives prostate cancer growth |
| title_sort | feedback loop between the androgen receptor and 6 phosphogluoconate dehydrogenase 6pgd drives prostate cancer growth |
| topic | pentose phosphate pathway prostate cancer androgen receptor |
| url | https://elifesciences.org/articles/62592 |
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