Publication Date:
2012-06-05
Description:
Overcoming metabolic stress is a critical step for solid tumour growth. However, the underlying mechanisms of cell death and survival under metabolic stress are not well understood. A key signalling pathway involved in metabolic adaptation is the liver kinase B1 (LKB1)-AMP-activated protein kinase (AMPK) pathway. Energy stress conditions that decrease intracellular ATP levels below a certain level promote AMPK activation by LKB1. Previous studies showed that LKB1-deficient or AMPK-deficient cells are resistant to oncogenic transformation and tumorigenesis, possibly because of the function of AMPK in metabolic adaptation. However, the mechanisms by which AMPK promotes metabolic adaptation in tumour cells are not fully understood. Here we show that AMPK activation, during energy stress, prolongs cell survival by redox regulation. Under these conditions, NADPH generation by the pentose phosphate pathway is impaired, but AMPK induces alternative routes to maintain NADPH and inhibit cell death. The inhibition of the acetyl-CoA carboxylases ACC1 and ACC2 by AMPK maintains NADPH levels by decreasing NADPH consumption in fatty-acid synthesis and increasing NADPH generation by means of fatty-acid oxidation. Knockdown of either ACC1 or ACC2 compensates for AMPK activation and facilitates anchorage-independent growth and solid tumour formation in vivo, whereas the activation of ACC1 or ACC2 attenuates these processes. Thus AMPK, in addition to its function in ATP homeostasis, has a key function in NADPH maintenance, which is critical for cancer cell survival under energy stress conditions, such as glucose limitations, anchorage-independent growth and solid tumour formation in vivo.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3607316/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3607316/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jeon, Sang-Min -- Chandel, Navdeep S -- Hay, Nissim -- AG016927/AG/NIA NIH HHS/ -- AG025953/AG/NIA NIH HHS/ -- CA090764/CA/NCI NIH HHS/ -- P60DK20595/DK/NIDDK NIH HHS/ -- R01 AG016927/AG/NIA NIH HHS/ -- R01 CA090764/CA/NCI NIH HHS/ -- England -- Nature. 2012 May 9;485(7400):661-5. doi: 10.1038/nature11066.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, Illinois 60607, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22660331" target="_blank"〉PubMed〈/a〉
Keywords:
AMP-Activated Protein Kinases/*metabolism
;
Acetyl-CoA Carboxylase/antagonists & inhibitors/metabolism
;
Animals
;
CHO Cells
;
Cell Death
;
Cell Line, Tumor
;
Cell Survival
;
Cell Transformation, Neoplastic
;
Contact Inhibition
;
Cricetinae
;
*Energy Metabolism
;
Enzyme Activation
;
Female
;
Glucose/deficiency
;
*Homeostasis
;
Hydrogen Peroxide/metabolism
;
Male
;
Mice
;
Mice, Nude
;
NADP/deficiency/*metabolism
;
Neoplasms/*metabolism/*pathology
;
Oxidation-Reduction
;
*Oxidative Stress
;
Protein-Serine-Threonine Kinases/deficiency/metabolism
;
Reactive Oxygen Species/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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