Format

Send to

Choose Destination
Nat Cell Biol. 2018 Jul;20(7):823-835. doi: 10.1038/s41556-018-0126-z. Epub 2018 Jun 18.

AMP kinase promotes glioblastoma bioenergetics and tumour growth.

Author information

1
Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
2
Department of Pathology and Laboratory Medicine, University of Pennsylvania, PA, USA.
3
Division of Molecular and Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
4
Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
5
Division of Center for Autoimmune Genomics and Etiology and Biomedical Informatics and Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
6
Division of Experimental Hematology and Cancer Biology, Cincinnati, OH, USA.
7
Sechenov University, Department of Biochemistry, Moscow, Russian Federation.
8
Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
9
Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, OH, USA.
10
Department of Neurosurgery, Brain Tumor Center, University of Cincinnati Neuroscience Institute and Mayfield Clinic, Cincinnati, OH, USA.
11
Department of Neurosurgery, University of Alabama, Cincinnati, OH, USA.
12
Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
13
Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. Biplab.dasgupta@cchmc.org.

Abstract

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 HIF1α 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.

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center