دورية أكاديمية
أعرض في EDS

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

التفاصيل البيبلوغرافية
العنوان: A feedback loop between the androgen receptor and 6-phosphogluoconate dehydrogenase (6PGD) drives prostate cancer growth.
المؤلفون: Gillis JL; Adelaide Medical School, University of Adelaide, Adelaide, Australia.; South Australian Health and Medical Research Institute, Adelaide, Australia., Hinneh JA; 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., Ryan NK; Adelaide Medical School, University of Adelaide, Adelaide, Australia.; South Australian Health and Medical Research Institute, Adelaide, Australia., Irani S; Adelaide Medical School, University of Adelaide, Adelaide, Australia.; South Australian Health and Medical Research Institute, Adelaide, Australia., Moldovan M; South Australian Health and Medical Research Institute, Adelaide, Australia., Quek LE; School of Mathematics and Statistics, Charles Perkins Centre, Faculty of Science, The University of Sydney, Camperdown, Australia., Shrestha RK; 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., Hanson AR; Flinders Health and Medical Research Institute, Flinders University, College of Medicine and Public Health, Bedford Park, Australia., Xie J; Flinders Health and Medical Research Institute, Flinders University, College of Medicine and Public Health, Bedford Park, Australia., Hoy AJ; School of Medical Sciences, Charles Perkins Centre, Faculty of Medicine and Health, The University of Sydney, Camperdown, Australia., Holst J; School of Medical Sciences and Prince of Wales Clinical School, University of New South Wales, Sydney, Australia., Centenera MM; 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., Mills IG; 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., Lynn DJ; 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., Selth LA; 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., Butler LM; 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.
المصدر: ELife [Elife] 2021 Aug 12; Vol. 10. Date of Electronic Publication: 2021 Aug 12.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: eLife Sciences Publications, Ltd Country of Publication: England NLM ID: 101579614 Publication Model: Electronic Cited Medium: Internet ISSN: 2050-084X (Electronic) Linking ISSN: 2050084X NLM ISO Abbreviation: Elife Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Cambridge, UK : eLife Sciences Publications, Ltd., 2012-
مواضيع طبية MeSH: Glyceraldehyde-3-Phosphate Dehydrogenases/*metabolism , Prostatic Neoplasms/*metabolism , Receptors, Androgen/*metabolism, AMP-Activated Protein Kinases/metabolism ; Acetyl-CoA Carboxylase/metabolism ; Cell Line ; Emodin/analogs & derivatives ; Feedback ; Gene Expression Regulation, Neoplastic ; Gene Knockdown Techniques ; Humans ; Male ; Mechanistic Target of Rapamycin Complex 1/metabolism ; Pentose Phosphate Pathway ; Prostatic Neoplasms/genetics ; Signal Transduction ; Sterol Regulatory Element Binding Protein 1/metabolism
مستخلص: 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- 13 C 2 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.
Competing Interests: JG, JH, NR, MM, LQ, RS, AH, JX, AH, JH, MC, IM, DL, LS, LB None, SI none
(© 2021, Gillis et al.)
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فهرسة مساهمة: Keywords: androgen receptor; cancer biology; human; pentose phosphate pathway; prostate cancer
سلسلة جزيئية: GEO GSE152254; GSE48403; GSE56288(GSM1358397); GSE56288(GSM1328950); GSE73994(GSM1907200); GSE91561(ENCFF911YFI); GSE31477(GSM935627;ENCFF000XXR)
المشرفين على المادة: 0 (AR protein, human)
0 (Receptors, Androgen)
0 (SREBF1 protein, human)
0 (Sterol Regulatory Element Binding Protein 1)
EC 1.2.1.- (Glyceraldehyde-3-Phosphate Dehydrogenases)
EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
EC 2.7.11.31 (AMP-Activated Protein Kinases)
EC 6.4.1.2 (ACACA protein, human)
EC 6.4.1.2 (Acetyl-CoA Carboxylase)
H6PT94IV61 (physcione)
KA46RNI6HN (Emodin)
تواريخ الأحداث: Date Created: 20210812 Date Completed: 20211021 Latest Revision: 20220107
رمز التحديث: 20221213
مُعرف محوري في PubMed: PMC8416027
DOI: 10.7554/eLife.62592
PMID: 34382934
قاعدة البيانات: MEDLINE
الوصف
تدمد:2050-084X
DOI:10.7554/eLife.62592