AMP kinase promotes glioblastoma bioenergetics and tumour growth.
AMP kinase promotes glioblastoma bioenergetics and tumour growth.
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DOI：
10.1038/s41556-018-0126-z
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发表时间：
2018-07
影响因子：
21.3
通讯作者：
Dasgupta B
中科院分区：
文献类型：
--
作者：
Chhipa RR;Fan Q;Anderson J;Muraleedharan R;Huang Y;Ciraolo G;Chen X;Waclaw R;Chow LM;Khuchua Z;Kofron M;Weirauch MT;Kendler A;McPherson C;Ratner N;Nakano I;Dasgupta N;Komurov K;Dasgupta B
压力是肿瘤演变的组成部分，癌细胞的存活取决于压力管理。我们发现，癌症相关的压力长期激活生物能传感器AMP激酶（AMPK），肿瘤细胞劫持正常细胞中保守的AMPK调节的应激反应途径，以生存。癌症基因组图谱（TCGA）数据的分析显示，AMPK亚型在致命的人类癌症胶质母细胞瘤（GBM）中高度表达。我们发现AMPK抑制降低了患者来源的GBM干细胞（GSC）和肿瘤的活力。在应激（运动）骨骼肌中，AMPK被激活，与cAMP反应元件结合蛋白-1（CREB 1）合作，促进葡萄糖代谢。我们证明致癌应激长期激活GSC中的AMPK，GSC通过转录因子HIF 1 α和GABPA选择AMPK-CREB 1通路来协调肿瘤生物能量学。最后，我们表明，成年小鼠耐受AMPK的系统性缺失，支持AMPK药理学抑制剂在GBM治疗中的效用。
Stress is integral to tumor evolution, and cancer cell survival depends on stress management. We found that cancer-associated stress chronically activate the bioenergetic sensor AMP kinase (AMPK), and tumor cells hijack an AMPK-regulated stress response pathway conserved in normal cells, to survive. Analysis of The Cancer Genome Atlas (TCGA) data revealed that AMPK isoforms are highly expressed in the lethal human cancer Glioblastoma (GBM). We show that AMPK inhibition reduces viability of patient-derived GBM stem cells (GSCs) and tumors. In stressed (exercised) skeletal muscle, AMPK is activated to cooperate with the cAMP response element binding protein-1 (CREB1) and promote glucose metabolism. We demonstrate that oncogenic stress chronically activates AMPK in GSCs that coopt the AMPK-CREB1 pathway to coordinate tumor bioenergetics through the transcription factors HIF1α and GABPA. Finally, we show that adult mice tolerate systemic deletion of AMPK supporting the utility of AMPK pharmacological inhibitors in the treatment of GBM.
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影响因子：
11.8
作者：
Dasgupta, Biplab;Milbrandt, Jeffrey
通讯作者：
Milbrandt, Jeffrey
影响因子：
64.8
作者：
Ernst, Jason;Kheradpour, Pouya;Mikkelsen, Tarjei S.;Shoresh, Noam;Ward, Lucas D.;Epstein, Charles B.;Zhang, Xiaolan;Wang, Li;Issner, Robbyn;Coyne, Michael;Ku, Manching;Durham, Timothy;Kellis, Manolis;Bernstein, Bradley E.
通讯作者：
Bernstein, Bradley E.
影响因子：
8.9
作者：
Hardie DG
通讯作者：
Hardie DG
影响因子：
50.3
作者：
Chae YC;Caino MC;Lisanti S;Ghosh JC;Dohi T;Danial NN;Villanueva J;Ferrero S;Vaira V;Santambrogio L;Bosari S;Languino LR;Herlyn M;Altieri DC
通讯作者：
Altieri DC
影响因子：
3.5
作者：
CARLING, D;ZAMMIT, VA;HARDIE, DG
通讯作者：
HARDIE, DG