Sleeping Beauty screen reveals Pparg activation in metastatic prostate cancer
Sleeping Beauty screen reveals Pparg activation in metastatic prostate cancer
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DOI：
10.1073/pnas.1601571113
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发表时间：
2016-07-19
影响因子：
11.1
通讯作者：
Leung, Hing Y.
中科院分区：
文献类型：
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作者：
Ahmad, Imran;Mui, Ernest;Leung, Hing Y.
前列腺癌（CaP）是发达国家最常见的成年男性癌症。预测前列腺肿瘤生物学的生物标志物的缺乏使得识别导致预后不良的关键途径和指导潜在的靶向治疗变得重要。在Pten-null背景下使用小鼠正向诱变筛选，我们发现过氧化物酶体增殖物激活受体γ (Pparg)编码配体激活的转录因子，通过激活脂质信号通路，包括上调脂质合成酶[脂肪酸合成酶（FASN），乙酰辅酶a羧化酶（ACC）， ATP柠檬酸裂解酶（ACLY）]，作为转移性CaP的启动子。重要的是，通过下调脂质合成程序，抑制PPARG在体内抑制肿瘤生长。我们发现PPARG水平升高与人类CaP中FASN水平升高密切相关，并且PPARG/FASN和PI3K/pAKT途径激活的高水平导致预后不良。这些数据表明，可以根据PPARG/FASN和PTEN水平对CaP患者进行分层，以确定可能对PPARG/FASN抑制反应良好的侵袭性CaP患者。
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.