Sleeping Beauty screen reveals Pparg activation in metastatic prostate cancer

Ahmad, I. et al. (2016) Sleeping Beauty screen reveals Pparg activation in metastatic prostate cancer. Proceedings of the National Academy of Sciences of the United States of America, 113(29), pp. 8290-8295. (doi:10.1073/pnas.1601571113) (PMID:27357679) (PMCID:PMC4961202)

Ahmad, I. et al. (2016) Sleeping Beauty screen reveals Pparg activation in metastatic prostate cancer. Proceedings of the National Academy of Sciences of the United States of America, 113(29), pp. 8290-8295. (doi:10.1073/pnas.1601571113) (PMID:27357679) (PMCID:PMC4961202)

[img]
Preview
Text
123789.pdf - Published Version

1MB

Abstract

Prostate cancer (CaP) is the most common adult male cancer in the developed world. The paucity of biomarkers to predict prostate tumor biology makes it important to identify key pathways that confer poor prognosis and guide potential targeted therapy. Using a murine forward mutagenesis screen in a Pten-null background, we identified peroxisome proliferator-activated receptor gamma (Pparg), encoding a ligand-activated transcription factor, as a promoter of metastatic CaP through activation of lipid signaling pathways, including up-regulation of lipid synthesis enzymes [fatty acid synthase (FASN), acetyl-CoA carboxylase (ACC), ATP citrate lyase (ACLY)]. Importantly, inhibition of PPARG suppressed tumor growth in vivo, with down-regulation of the lipid synthesis program. We show that elevated levels of PPARG strongly correlate with elevation of FASN in human CaP and that high levels of PPARG/FASN and PI3K/pAKT pathway activation confer a poor prognosis. These data suggest that CaP patients could be stratified in terms of PPARG/FASN and PTEN levels to identify patients with aggressive CaP who may respond favorably to PPARG/FASN inhibition.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Ahmad, Dr Imran and Tan, Dr Ee and Markert, Dr Elke and Leung, Professor Hing and Loveridge, Ms Carolyn and Repiscak, Dr Peter and Mui, Mr Ernest and Salji, Dr Mark and Edwards, Professor Joanne and Patel, Dr Rachana and Galbraith, Dr Laura and Sansom, Professor Owen
Authors: Ahmad, I., Mui, E., Galbraith, L., Patel, R., Tan, E. H., Salji, M., Rust, A. G., Repiscak, P., Hedley, A., Markert, E., Loveridge, C., van der Weyden, L., Edwards, J., Sansom, O. J., Adams, D. J., and Leung, H. Y.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Proceedings of the National Academy of Sciences of the United States of America
Publisher:National Academy of Sciences
ISSN:0027-8424
ISSN (Online):1091-6490
Copyright Holders:Copyright © 2016 The Authors
First Published:First published in Proceedings of the National Academy of Sciences of the United States of America 113(26):8290-8295
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

University Staff: Request a correction | Enlighten Editors: Update this record

Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
676071Identification and Validation of New Therapeutic Targets in Enzalutamide-Resistant Prostate CancerImran AhmadCancer Research UK (CAN-RES-UK)19661RI CANCER SCIENCES