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)
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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, Professor Imran and Tan, Dr Ee and Leung, Professor Hing and Salji, Dr Mark and Mui, Mr Ernest and Edwards, Professor Joanne and Markert, Dr Elke and Repiscak, Dr Peter and Patel, Dr Rachana and Loveridge, Dr Carolyn 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 > School 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 |
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