PGC1α promotes tumor growth by inducing gene expression programs supporting lipogenesis.
PGC1α promotes tumor growth by inducing gene expression programs supporting lipogenesis.
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DOI：
10.1158/0008-5472.can-11-1011
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发表时间：
2011-11-01
期刊：
影响因子：
11.2
通讯作者：
Girnun GD
中科院分区：
文献类型：
--
作者：
Bhalla K;Hwang BJ;Dewi RE;Ou L;Twaddel W;Fang HB;Vafai SB;Vazquez F;Puigserver P;Boros L;Girnun GD
尽管有氧糖酵解在癌症中的作用，但最近的研究强调了线粒体和生物合成途径的重要性。过氧化物酶体增殖物激活受体γ共激活因子1α（PGC 1 α）是氧化代谢和脂肪生成等多种代谢途径的关键转录调控因子。最初的研究表明，与邻近的正常组织相比，肿瘤中的PGC 1 α表达减少。巧合的是，其他研究表明PGC 1 α与癌细胞增殖有关。因此，PGC 1 α在癌症，尤其是癌发生中的作用尚不清楚。使用Pgc 1 α-/-和Pgc 1 α+/+小鼠，我们表明PGC 1 α的缺失可保护小鼠免受氧化偶氮甲烷诱导的结肠癌发生。同样，与Pgc 1 α+/+小鼠相比，Pgc 1 α-/-小鼠中二乙基亚硝胺诱导的肝癌发生减少。使用PGC 1 α表达的获得和丧失的异种移植物研究表明，PGC 1 α也促进肿瘤生长。有趣的是，虽然PGC 1 α诱导氧化磷酸化和TCA循环基因表达，但我们还观察到从头脂肪酸合成所需的两个基因ACC和FXR的表达增加。此外，PGC 1 α还增加了葡萄糖转化为乙酰辅酶A以合成脂肪酸所需的SLC 25 A1和ACLY，从而将PGC 1 α的氧化和脂肪生成功能联系起来。事实上，使用13 C稳定同位素示踪分析，我们表明，PGC 1 α增加从头脂肪生成。重要的是，脂肪酸合成的抑制减弱了PGC 1 α的这些促生长作用。总之，这些研究首次表明，PGC 1 α的缺失可防止肿瘤发生，并且PGC 1 α协调调节线粒体和脂肪酸代谢以促进肿瘤生长。
Despite the role of aerobic glycolysis in cancer, recent studies highlight the importance of the mitochondria and biosynthetic pathways as well. PPARγ coactivator 1α (PGC1α) is a key transcriptional regulator of several metabolic pathways including oxidative metabolism and lipogenesis. Initial studies suggested that PGC1α expression is reduced in tumors compared to adjacent normal tissue. Paradoxically, other studies show that PGC1α is associated with cancer cell proliferation. Therefore the role of PGC1α in cancer and especially carcinogenesis is unclear. Using Pgc1α-/- and Pgc1α+/+ mice we show that loss of PGC1α protects mice from azoxymethane induced colon carcinogenesis. Similarly, diethylnitrosamine induced liver carcinogenesis is reduced in Pgc1α-/- mice compared to Pgc1α+/+ mice. Xenograft studies using gain and loss of PGC1α expression demonstrated that PGC1α also promotes tumor growth. Interestingly, while PGC1α induced oxidative phosphorylation and TCA cycle gene expression, we also observed an increase in the expression of two genes required for de novo fatty acid synthesis, ACC and FASN. In addition, SLC25A1 and ACLY, which are required for the conversion of glucose in to acetyl CoA for fatty acid synthesis, were also increased by PGC1α, thus linking the oxidative and lipogenic functions of PGC1α. Indeed, using 13C stable isotope tracer analysis we show that PGC1α increased de novo lipogenesis. Importantly, inhibition of fatty acid synthesis blunted these progrowth effects of PGC1α. In conclusion, these studies show for the first time that loss of PGC1α protects against carcinogenesis and that PGC1α coordinately regulates mitochondrial and fatty acid metabolism to promote tumor growth.