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...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	eLife Sciences Publications Ltd 2021
Materias:	pentose phosphate pathway prostate cancer androgen receptor Medicine R Science Q Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/7b041890c6d2431cb95c6683b6ee5211
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:7b041890c6d2431cb95c6683b6ee5211
record_format	dspace
spelling	oai:doaj.org-article:7b041890c6d2431cb95c6683b6ee52112021-11-25T08:31:13ZA feedback loop between the androgen receptor and 6-phosphogluoconate dehydrogenase (6PGD) drives prostate cancer growth10.7554/eLife.625922050-084Xe62592https://doaj.org/article/7b041890c6d2431cb95c6683b6ee52112021-08-01T00:00:00Zhttps://elifesciences.org/articles/62592https://doaj.org/toc/2050-084XAlterations 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.Joanna L GillisJosephine A HinnehNatalie K RyanSwati IraniMax MoldovanLake-Ee QuekRaj K ShresthaAdrienne R HansonJianling XieAndrew J HoyJeff HolstMargaret M CenteneraIan G MillsDavid J LynnLuke A SelthLisa M ButlereLife Sciences Publications Ltdarticlepentose phosphate pathwayprostate cancerandrogen receptorMedicineRScienceQBiology (General)QH301-705.5ENeLife, Vol 10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	pentose phosphate pathway prostate cancer androgen receptor Medicine R Science Q Biology (General) QH301-705.5
spellingShingle	pentose phosphate pathway prostate cancer androgen receptor Medicine R Science Q Biology (General) QH301-705.5 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
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.
format	article
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
title	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_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_sort	feedback loop between the androgen receptor and 6-phosphogluoconate dehydrogenase (6pgd) drives prostate cancer growth
publisher	eLife Sciences Publications Ltd
publishDate	2021
url	https://doaj.org/article/7b041890c6d2431cb95c6683b6ee5211
work_keys_str_mv	AT joannalgillis afeedbackloopbetweentheandrogenreceptorand6phosphogluoconatedehydrogenase6pgddrivesprostatecancergrowth AT josephineahinneh afeedbackloopbetweentheandrogenreceptorand6phosphogluoconatedehydrogenase6pgddrivesprostatecancergrowth AT nataliekryan afeedbackloopbetweentheandrogenreceptorand6phosphogluoconatedehydrogenase6pgddrivesprostatecancergrowth AT swatiirani afeedbackloopbetweentheandrogenreceptorand6phosphogluoconatedehydrogenase6pgddrivesprostatecancergrowth AT maxmoldovan afeedbackloopbetweentheandrogenreceptorand6phosphogluoconatedehydrogenase6pgddrivesprostatecancergrowth AT lakeeequek afeedbackloopbetweentheandrogenreceptorand6phosphogluoconatedehydrogenase6pgddrivesprostatecancergrowth AT rajkshrestha afeedbackloopbetweentheandrogenreceptorand6phosphogluoconatedehydrogenase6pgddrivesprostatecancergrowth AT adriennerhanson afeedbackloopbetweentheandrogenreceptorand6phosphogluoconatedehydrogenase6pgddrivesprostatecancergrowth AT jianlingxie afeedbackloopbetweentheandrogenreceptorand6phosphogluoconatedehydrogenase6pgddrivesprostatecancergrowth AT andrewjhoy afeedbackloopbetweentheandrogenreceptorand6phosphogluoconatedehydrogenase6pgddrivesprostatecancergrowth AT jeffholst afeedbackloopbetweentheandrogenreceptorand6phosphogluoconatedehydrogenase6pgddrivesprostatecancergrowth AT margaretmcentenera afeedbackloopbetweentheandrogenreceptorand6phosphogluoconatedehydrogenase6pgddrivesprostatecancergrowth AT iangmills afeedbackloopbetweentheandrogenreceptorand6phosphogluoconatedehydrogenase6pgddrivesprostatecancergrowth AT davidjlynn afeedbackloopbetweentheandrogenreceptorand6phosphogluoconatedehydrogenase6pgddrivesprostatecancergrowth AT lukeaselth afeedbackloopbetweentheandrogenreceptorand6phosphogluoconatedehydrogenase6pgddrivesprostatecancergrowth AT lisambutler afeedbackloopbetweentheandrogenreceptorand6phosphogluoconatedehydrogenase6pgddrivesprostatecancergrowth AT joannalgillis feedbackloopbetweentheandrogenreceptorand6phosphogluoconatedehydrogenase6pgddrivesprostatecancergrowth AT josephineahinneh feedbackloopbetweentheandrogenreceptorand6phosphogluoconatedehydrogenase6pgddrivesprostatecancergrowth AT nataliekryan feedbackloopbetweentheandrogenreceptorand6phosphogluoconatedehydrogenase6pgddrivesprostatecancergrowth AT swatiirani feedbackloopbetweentheandrogenreceptorand6phosphogluoconatedehydrogenase6pgddrivesprostatecancergrowth AT maxmoldovan feedbackloopbetweentheandrogenreceptorand6phosphogluoconatedehydrogenase6pgddrivesprostatecancergrowth AT lakeeequek feedbackloopbetweentheandrogenreceptorand6phosphogluoconatedehydrogenase6pgddrivesprostatecancergrowth AT rajkshrestha feedbackloopbetweentheandrogenreceptorand6phosphogluoconatedehydrogenase6pgddrivesprostatecancergrowth AT adriennerhanson feedbackloopbetweentheandrogenreceptorand6phosphogluoconatedehydrogenase6pgddrivesprostatecancergrowth AT jianlingxie feedbackloopbetweentheandrogenreceptorand6phosphogluoconatedehydrogenase6pgddrivesprostatecancergrowth AT andrewjhoy feedbackloopbetweentheandrogenreceptorand6phosphogluoconatedehydrogenase6pgddrivesprostatecancergrowth AT jeffholst feedbackloopbetweentheandrogenreceptorand6phosphogluoconatedehydrogenase6pgddrivesprostatecancergrowth AT margaretmcentenera feedbackloopbetweentheandrogenreceptorand6phosphogluoconatedehydrogenase6pgddrivesprostatecancergrowth AT iangmills feedbackloopbetweentheandrogenreceptorand6phosphogluoconatedehydrogenase6pgddrivesprostatecancergrowth AT davidjlynn feedbackloopbetweentheandrogenreceptorand6phosphogluoconatedehydrogenase6pgddrivesprostatecancergrowth AT lukeaselth feedbackloopbetweentheandrogenreceptorand6phosphogluoconatedehydrogenase6pgddrivesprostatecancergrowth AT lisambutler feedbackloopbetweentheandrogenreceptorand6phosphogluoconatedehydrogenase6pgddrivesprostatecancergrowth
_version_	1718413567117492224

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

Ejemplares similares