| Title: |
A feedback loop between the 1 androgen receptor and 6-phosphogluoconate dehydrogenase (6PGD) drives prostate cancer growth: Cooperativity between 6PGD and AR drives prostate cancer growth |
| Authors: |
Gillis, JL; Hinneh, JA; Ryan, N; Irani, S; Moldovan, M; Quek, LE; Shrestha, R; Hanson, AR; Xie, J; Hoy, AJ; Holst, J; Centenera, MM; Mills, IG; Lynn, DJ; Selth, LA; Butler, LM |
| Source: |
urn:ISSN:2050-084X ; Elife, 10, e62592 |
| Publisher Information: |
eLife |
| Publication Year: |
2021 |
| Collection: |
UNSW Sydney (The University of New South Wales): UNSWorks |
| Subject Terms: |
3101 Biochemistry and Cell Biology; 32 Biomedical and Clinical Sciences; 31 Biological Sciences; 3202 Clinical Sciences; 3211 Oncology and Carcinogenesis; Aging; Urologic Diseases; Cancer; Genetics; Prostate Cancer; 2.1 Biological and endogenous factors; 5.1 Pharmaceuticals; AMP-Activated Protein Kinases; Acetyl-CoA Carboxylase; Cell Line; Emodin; Feedback; Gene Expression Regulation; Neoplastic; Gene Knockdown Techniques; Glyceraldehyde-3-Phosphate Dehydrogenases; Humans; Male; Mechanistic Target of Rapamycin Complex 1; Pentose Phosphate Pathway; Prostatic Neoplasms; Receptors; Androgen; Signal Transduction; Sterol Regulatory Element Binding Protein 1 |
| 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 ACC1 and mTOR; 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 PGD, 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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
unknown |
| Relation: |
https://hdl.handle.net/1959.4/unsworks_82538; https://doi.org/10.7554/eLife.62592 |
| DOI: |
10.7554/eLife.62592 |
| Availability: |
https://hdl.handle.net/1959.4/unsworks_82538; https://unsworks.unsw.edu.au/bitstreams/5e5e8f4c-1ffe-43ff-b76c-bc69dc5d3fe4/download; https://doi.org/10.7554/eLife.62592 |
| Rights: |
open access ; https://purl.org/coar/access_right/c_abf2 ; CC BY ; https://creativecommons.org/licenses/by/4.0/ ; free_to_read |
| Accession Number: |
edsbas.7FCCF54C |
| Database: |
BASE |