PGC1α promotes cholangiocarcinoma metastasis by upregulating PDHA1 and MPC1 expression to reverse the Warburg effect.
PGC1α promotes cholangiocarcinoma metastasis by upregulating PDHA1 and MPC1 expression to reverse the Warburg effect.
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DOI：
10.1038/s41419-018-0494-0
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发表时间：
2018-05-01
影响因子：
9
通讯作者：
Jiang H
中科院分区：
文献类型：
--
作者：
Dan Li;Wang C;Ma P;Yu Q;Gu M;Dong L;Jiang W;Pan S;Xie C;Han J;Lan Y;Sun J;Sheng P;Liu K;Wu Y;Liu L;Ma Y;Jiang H
PGC 1 α作为线粒体代谢的中心调节因子，其在癌症进展中的作用已被强调，但在很大程度上仍不明确。尤其是PGC 1 α对胆管癌（cholangiocarcinoma，CCA）的作用尚不清楚。我们发现，尽管与邻近正常组织相比，PGC 1 α在CCA中的表达降低，但PGC 1 α过表达对CCA生长没有影响。相反，PGC 1 α过表达促进CCA转移在体外和体内。从机制上讲，我们首次阐明了PGC 1 α通过上调丙酮酸脱氢酶E1 α 1亚基和线粒体丙酮酸载体1的表达来逆转瓦尔堡效应，从而增加丙酮酸流入线粒体进行氧化，同时促进线粒体生物合成和融合以介导代谢转换为氧化磷酸化。一方面，线粒体氧化代谢的增强与活性氧（ROS）的产生有关;另一方面，PGC 1 α表达的增加上调了几种ROS解毒酶的mRNA表达水平。为此，升高但低于临界阈值的ROS水平不抑制CCA细胞增殖。ROS的适度增加促进了CCA细胞的转移扩散，抗氧化剂可以消除这种作用。我们的研究表明，开发PGC 1 α靶向治疗或阻断PGC 1 α信号轴抑制CCA转移的潜在效用。
PGC1α acts as a central regulator of mitochondrial metabolism, whose role in cancer progression has been highlighted but remains largely undefined. Especially, it is completely unknown about the effect of PGC1α on cholangiocarcinoma (CCA). Here we showed that PGC1α overexpression had no impact on CCA growth despite the decreased expression of PGC1α in CCA compared with adjacent normal tissue. Instead, PGC1α overexpression-promoted CCA metastasis both in vitro and in vivo. Mechanistically, for the first time, we illuminated that PGC1α reversed the Warburg effect by upregulating the expression of pyruvate dehydrogenase E1 alpha 1 subunit and mitochondrial pyruvate carrier 1 to increase pyruvate flux into the mitochondria for oxidation, whereas simultaneously promoting mitochondrial biogenesis and fusion to mediate the metabolic switch to oxidative phosphorylation. On the one hand, enhanced mitochondrial oxidation metabolism correlated with elevated reactive oxygen species (ROS) production; on the other hand, increased PGC1α expression upregulated the expression levels of mRNA for several ROS-detoxifying enzymes. To this end, the ROS levels, which were elevated but below a critical threshold, did not inhibit CCA cells proliferation. And the moderately increased ROS facilitated metastatic dissemination of CCA cells, which can be abrogated by antioxidants. Our study suggests the potential utility of developing the PGC1α-targeted therapies or blocking PGC1α signaling axis for inhibiting CCA metastasis.
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DOI：
10.1042/bj20081386
发表时间：
2009-01-01
期刊：
The Biochemical journal
影响因子：
--
作者：
Murphy MP
通讯作者：
Murphy MP
影响因子：
50.3
作者：
Vazquez F;Lim JH;Chim H;Bhalla K;Girnun G;Pierce K;Clish CB;Granter SR;Widlund HR;Spiegelman BM;Puigserver P
通讯作者：
Puigserver P
影响因子：
29.4
作者：
Ilyas SI;Gores GJ
通讯作者：
Gores GJ
影响因子：
9.7
作者：
Lu, Jianrong;Tan, Ming;Cai, Qingsong
通讯作者：
Cai, Qingsong
影响因子：
64.8
作者：
Piskounova E;Agathocleous M;Murphy MM;Hu Z;Huddlestun SE;Zhao Z;Leitch AM;Johnson TM;DeBerardinis RJ;Morrison SJ
通讯作者：
Morrison SJ