AMP kinase promotes glioblastoma bioenergetics and tumour growth
Chhipa R. R., Fan Q., Anderson J., Muraleedharan R., Huang Y., Ciraolo G., Chen X., Waclaw R., Chow L. M., Khuchua Z. A., Kofron M., Weirauch M. T., Kendler A., McPherson C., Ratner N., Nakano I., Dasgupta N., Komurov K., Dasgupta B.
Nature Cell Biology
Vol.20, Issue7, P. 823-835
Опубликовано: 2018
Тип ресурса: Статья
DOI:10.1038/s41556-018-0126-z
Аннотация:
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 pharmacologic
Ключевые слова:
adenylate kinase; cyclic AMP responsive element binding protein; GA binding protein; hypoxia inducible factor 1alpha; mammalian target of rapamycin; antineoplastic agent; CREB1 protein, human; cyclic AMP responsive element binding protein; GA binding protein; GABPA protein, human; HIF1A protein, human; hydroxymethylglutaryl coenzyme A reductase kinase; hypoxia inducible factor 1alpha; PRKAB1 protein, human; protein kinase inhibitor; adult; animal experiment; animal model; Article; autophagy; bioenergy; cancer inhibition; cancer mortality; cancer stem cell; cancer survival; cell activation; cell death; cell survival; cell viability; cellular stress response; controlled study; down regulation; female; glioblastoma; glucose metabolism; human; human cell; human tissue; male; mouse; nonhuman; primary tumor; priority journal; protein depletion; protein expression; protein phosphorylation; signal transduction; skeletal muscle cell; tumor cell; tumor growth; tumor promotion; animal; antagonist
Язык текста: Английский
ISSN: 1476-4679
Chhipa R. R.
Fan Q.
Anderson J.
Muraleedharan R.
Huang Y.
Ciraolo G.
Chen X.
Waclaw R.
Chow L. M.
Khuchua Z. A. Zaza Avtandilovich 1957-
Kofron M.
Weirauch M. T.
Kendler A.
McPherson C.
Ratner N.
Nakano I.
Dasgupta N.
Komurov K.
Dasgupta B.
Чхипа Р. Р.
Фан Q.
Андерсон Й.
Муралеедхаран Р.
Хуанг Y.
Cираоло Г.
Чен Х.
Wаcлаw Р.
Чоw Л. М.
Хучуа З. А. Заза Автандилович 1957-
Кофрон М.
Wеирауч М. Т.
Кендлер А.
МcПхерсон C.
Ратнер Н.
Накано И.
Дасгупта Н.
Комуров К.
Дасгупта Б.
AMP kinase promotes glioblastoma bioenergetics and tumour growth
Текст визуальный непосредственный
Nature Cell Biology
Nature Publishing Group
Vol.20, Issue7 P. 823-835
2018
Статья
adenylate kinase cyclic AMP responsive element binding protein GA binding protein hypoxia inducible factor 1alpha mammalian target of rapamycin antineoplastic agent CREB1 protein, human cyclic AMP responsive element binding protein GA binding protein GABPA protein, human HIF1A protein, human hydroxymethylglutaryl coenzyme A reductase kinase hypoxia inducible factor 1alpha PRKAB1 protein, human protein kinase inhibitor adult animal experiment animal model Article autophagy bioenergy cancer inhibition cancer mortality cancer stem cell cancer survival cell activation cell death cell survival cell viability cellular stress response controlled study down regulation female glioblastoma glucose metabolism human human cell human tissue male mouse nonhuman primary tumor priority journal protein depletion protein expression protein phosphorylation signal transduction skeletal muscle cell tumor cell tumor growth tumor promotion animal antagonist
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 pharmacologic