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Cancer Biol Ther. 2014 Feb;15(2):156-69. doi: 10.4161/cbt.26726. Epub 2013 Nov 1.

AMP-activated protein kinase (AMPK) beyond metabolism: a novel genomic stress sensor participating in the DNA damage response pathway.

Author information

1
Translational Radiation Biology Laboratory; Juravinski Cancer Center; Hamilton, ON Canada; Department of Oncology; McMaster University; Hamilton, ON Canada.
2
Department of Medicine; McMaster University; Hamilton, ON Canada.
3
Department of Pathology and Molecular Medicine; McMaster University; Hamilton, ON Canada.

Abstract

AMP-activated protein kinase (AMPK), an established metabolic stress sensor, has gained popularity in cancer biology due to its ability to control cellular growth and mediate cell cycle checkpoints in cancer cells in response to low energy levels. AMPK is a key effector of the tumor suppressor liver kinase B 1 (LKB1) which inhibits the cellular growth mediator mammalian target of rapamycin (mTOR) and activates checkpoint mediators such as p53 and the cyclin dependent kinase inhibitors p21(cip1) and p27(kip1). However, recent work describes a novel function for AMPK as a sensor of genomic stress and a participant of the DNA damage response (DDR) pathway. Ionizing radiation and chemotherapy activate AMPK in cancer cells to mediate signal transduction downstream of ataxia telangiectasia mutated (ATM) to activate p53- p21(cip1)/p27(kip1) and inhibit mTOR. We discuss evidence on the transcriptional and post-translational regulation of AMPK by ionizing radiation and the role of the enzyme as a mediator of chemo- and radiation sensitivity in epithelial cancer cells. Furthermore, we review data on the participation of AMPK in cytokinesis and observations suggesting a physical association of this enzyme with the mitotic apparatus. The evidence available to date suggests that AMPK is a point of convergence of metabolic and genomic stress signals, which (1) control the activity of growth mediators, (2) propagate DDR, and (3) mediate the anti-proliferative effects of common cytotoxic cancer therapy such as radiation and chemotherapy. This highlights the importance of targeting AMPK with novel cancer therapeutics.

KEYWORDS:

AMPK; ATM; cell cycle; ionizing radiation; mitosis

PMID:
24100703
PMCID:
PMC3928130
DOI:
10.4161/cbt.26726
[Indexed for MEDLINE]
Free PMC Article

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