AMP kinase promotes glioblastoma bioenergetics and tumour growth

作者：Chhipa Rishi Raj; Fan Qiang; Anderson Jane; Muraleedharan Ranjithmenon; Huang Yan; Ciraolo Georgianne; Chen Xiaoting; Waclaw Ronald; Chow Lionel M; Khuchua Zaza; Kofron Matthew; Weirauch Matthew T; Kendler Ady; McPherson Christopher; Ratner Nancy; Nakano Ichiro; Dasgupta Nupur; Komurov Kakajan; Dasgupta Biplab^*

来源：Nature Cell Biology, 2018, 20(7): 823-+.

DOI：10.1038/s41556-018-0126-z

Stress is integral to tumour evolution, and cancer cell survival depends on stress management. We found that cancer-associated stress chronically activates the bioenergetic sensor AMP kinase (AMPK) and, to survive, tumour cells hijack an AMPK-regulated stress response pathway conserved in normal cells. Analysis of The Cancer Genome Atlas 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 tumours. In stressed (exercised) skeletal muscle, AMPK is activated to cooperate with CREB1 (cAMP response element binding protein-1) and promote glucose metabolism. We demonstrate that oncogenic stress chronically activates AMPK in GSCs that coopt the AMPK-CREB1 pathway to coordinate tumour bioenergetics through the transcription factors HIF1 alpha and GABPA. Finally, we show that adult mice tolerate systemic deletion of AMPK, supporting the use of AMPK pharmacological inhibitors in the treatment of GBM.

• 出版日期2018-7