Sleeping Beauty screen reveals Pparg activation in metastatic prostate cancer

被引：93

作者：

Ahmad, Imran ^{[1
,2
]}

Mui, Ernest ^{[1
,2
]}

Galbraith, Laura ^{[1
,2
]}

Patel, Rachana ^{[1
,2
]}

Tan, Ee Hong ^{[1
,2
]}

Salji, Mark ^{[1
,2
]}

Rust, Alistair G. ^{[3
]}

Repiscak, Peter ^{[1
,2
]}

Hedley, Ann ^{[1
]}

Markert, Elke ^{[1
]}

Loveridge, Carolyn ^{[1
,2
]}

van der Weyden, Louise ^{[3
]}

Edwards, Joanne ^{[2
]}

Sansom, Owen J. ^{[1
]}

Adams, David J. ^{[3
]}

Leung, Hing Y. ^{[1
,2
]}

机构：

[1] Cancer Res UK Beatson Inst, Glasgow G61 1BD, Lanark, Scotland

[2] Univ Glasgow, Inst Canc Sci, Glasgow G61 1QH, Lanark, Scotland

[3] Wellcome Trust Sanger Inst, Expt Canc Genet, Cambridge CB10 1SA, England

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2016年 / 113卷 / 29期

关键词：

PTEN; PPARG; Sleeping Beauty; prostate cancer; metastasis; TUMOR-SUPPRESSOR GENE; RECEPTOR-GAMMA; EPITHELIAL-CELLS; EXPRESSION; PTEN; TUMORIGENESIS; LIGAND; GW9662; LIPOGENESIS; SENESCENCE;

D O I：

10.1073/pnas.1601571113

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：8290 / 8295

页数：6

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