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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.

In the version of this Article originally published, the competing interests statement was missing. The authors declare no competing interests; this statement has now been added in all online versions of the Article.