The Anti-Warburg Effect Elicited by the cAMP-PGC1α Pathway Drives Differentiation of Glioblastoma Cells into Astrocytes.
The Anti-Warburg Effect Elicited by the cAMP-PGC1α Pathway Drives Differentiation of Glioblastoma Cells into Astrocytes.
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cAMP-PGC1 α 通路引发的抗 Warburg 效应驱动胶质母细胞瘤细胞分化为星形胶质细胞
DOI：
10.1016/j.celrep.2016.12.037
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发表时间：
2017-01-10
期刊：
影响因子：
8.8
通讯作者：
Yan G
中科院分区：
文献类型：
--
作者：
Xing F;Luan Y;Cai J;Wu S;Mai J;Gu J;Zhang H;Li K;Lin Y;Xiao X;Liang J;Li Y;Chen W;Tan Y;Sheng L;Lu B;Lu W;Gao M;Qiu P;Su X;Yin W;Hu J;Chen Z;Sai K;Wang J;Chen F;Chen Y;Zhu S;Liu D;Cheng S;Xie Z;Zhu W;Yan G
多形性胶质母细胞瘤 (GBM) 是最具侵袭性的人类癌症之一。尽管分化疗法已被提议作为治疗 GBM 的潜在方法，但诱导分化的机制仍不清楚。在这里，我们使用 cAMP 激活剂建立了 GBM 诱导分化模型，该激活剂特异性引导 GBM 分化为星形胶质细胞。转录组学和蛋白质组学分析表明，氧化磷酸化和线粒体生物发生参与 GBM 的诱导分化。二丁酰环 AMP (dbcAMP) 可以逆转 Warburg 效应，耗氧量增加和乳酸生成减少就证明了这一点。 CREB-PGC1α 通路激活诱导的线粒体生物发生触发代谢转变和分化。使用 mdivi1 或通过沉默 PGC1α 来阻断线粒体生物合成会消除分化；相反，PGC1α 的过度表达会引发分化。在 GBM 异种移植模型和患者来源的 GBM 样本中，cAMP 激活剂还可诱导肿瘤生长抑制和分化。我们的数据表明线粒体生物发生和代谢转变为氧化磷酸化驱动肿瘤细胞的分化。简述 Xing 等人。研究表明，从糖酵解到氧化磷酸化的代谢转变通过 cAMP 激活驱动 GBM 细胞分化为星形胶质细胞。从机制上讲，cAMP-CREB-PGC1α 信号介导线粒体生物发生，从而导致代谢重编程、诱导分化和肿瘤生长抑制。
Glioblastoma multiforme (GBM) is among the most aggressive of human cancers. Although differentiation therapy has been proposed as a potential approach to treat GBM, the mechanisms of induced differentiation remain poorly defined. Here, we established an induced differentiation model of GBM using cAMP activators that specifically directed GBM differentiation into astroglia. Transcriptomic and proteomic analyses revealed that oxidative phosphorylation and mitochondrial biogenesis are involved in induced differentiation of GBM. Dibutyryl cyclic AMP (dbcAMP) reverses the Warburg effect, as evidenced by increased oxygen consumption and reduced lactate production. Mitochondrial biogenesis induced by activation of the CREB-PGC1α pathway triggers metabolic shift and differentiation. Blocking mitochondrial biogenesis using mdivi1 or by silencing PGC1α abrogates differentiation; conversely, overexpression of PGC1α elicits differentiation. In GBM xenograft models and patient-derived GBM samples, cAMP activators also induce tumor growth inhibition and differentiation. Our data show that mitochondrial biogenesis and metabolic switch to oxidative phosphorylation drive the differentiation of tumor cells. In Brief Xing et al. show that the metabolic shift from glycolysis to oxidative phosphorylation drives differentiation of GBM cells into astrocytes by cAMP activation. Mechanistically, the cAMP-CREB-PGC1α signal mediates mitochondrial biogenesis, which leads to metabolic reprogramming, induced differentiation, and tumor growth inhibition.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
DOI：
10.1038/nrm3772
发表时间：
2014-04
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
14.9
作者：
Flicek P;Amode MR;Barrell D;Beal K;Billis K;Brent S;Carvalho-Silva D;Clapham P;Coates G;Fitzgerald S;Gil L;Girón CG;Gordon L;Hourlier T;Hunt S;Johnson N;Juettemann T;Kähäri AK;Keenan S;Kulesha E;Martin FJ;Maurel T;McLaren WM;Murphy DN;Nag R;Overduin B;Pignatelli M;Pritchard B;Pritchard E;Riat HS;Ruffier M;Sheppard D;Taylor K;Thormann A;Trevanion SJ;Vullo A;Wilder SP;Wilson M;Zadissa A;Aken BL;Birney E;Cunningham F;Harrow J;Herrero J;Hubbard TJ;Kinsella R;Muffato M;Parker A;Spudich G;Yates A;Zerbino DR;Searle SM
通讯作者：
Searle SM
DOI：
10.1158/1078-0432.ccr-08-0827
发表时间：
2008-12-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Goldhoff P;Warrington NM;Limbrick DD Jr;Hope A;Woerner BM;Jackson E;Perry A;Piwnica-Worms D;Rubin JB
通讯作者：
Rubin JB
影响因子：
64.5
作者：
Hsu, Peggy P.;Sabatini, David M.
通讯作者：
Sabatini, David M.