Abstract
AMP-activated protein kinase (AMPK) is a key regulator of cellular energy balance. In response to metabolic stress, it acts to redress energy imbalance through promotion of ATP-generating catabolic processes and inhibition of ATP-consuming processes, including cell growth and proliferation. While findings that AMPK was a downstream effector of the tumour suppressor LKB1 indicated that it might act to repress tumourigenesis, more recent evidence suggests that AMPK can either suppress or promote cancer, depending on the context. Prior to tumourigenesis AMPK may indeed restrain aberrant growth, but once a cancer has arisen, AMPK may instead support survival of the cancer cells by adjusting their rate of growth to match their energy supply, as well as promoting genome stability. The two isoforms of the AMPK catalytic subunit may have distinct functions in human cancers, with the AMPK-α1 gene often being amplified, while the AMPK-α2 gene is more often mutated. The prevalence of metabolic disorders, such as obesity and Type 2 diabetes, has led to the development of a wide range of AMPK-activating drugs. While these might be useful as preventative therapeutics in individuals predisposed to cancer, it seems more likely that AMPK inhibitors, whose development has lagged behind that of activators, would be efficacious for the treatment of pre-existing cancers.
Highlights
The AMP-activated protein kinase (AMPK) is the central component of a signaling pathway that is conserved in essentially all eukaryotes, the exceptions being a few parasites (e.g., Plasmodium falciparum, the causative agent of malaria) that spend most of their life cycle living inside other eukaryotic cells, in which case the host cell provides AMPK and the parasite may have been able to dispense with it [1,2,3]
In 2000, two groups reported that metformin and phenformin were inhibitors of Complex I of the respiratory chain [106,107], and the following year it was reported have been various proposals to explain the mechanism of action of biguanides other than by inhibition of Complex I and other than by AMPK activation [109,110], there is general agreement that these drugs do indirectly activate AMPK
The probability (p) that this would occur by random chance if the two genes were behaving independently was
Summary
The AMP-activated protein kinase (AMPK) is the central component of a signaling pathway that is conserved in essentially all eukaryotes, the exceptions being a few parasites (e.g., Plasmodium falciparum, the causative agent of malaria) that spend most of their life cycle living inside other eukaryotic cells, in which case the host cell provides AMPK and the parasite may have been able to dispense with it [1,2,3]. Glucose deprivation can cause increases in AMP:ATP and ADP:ATP ratios in cells that are dependent upon glycolysis, in other cells this lysosomal pathway of AMPK activation can occur without any changes in these ratios [6]. A non-canonical pathway involving activation, by rising intracellular Ca2+ , of the calcium/calmodulin-dependent kinase CaMKK2 which, like LKB1, phosphorylates. A non-canonical pathway in which AMPK is activated by DNA-damaging treatments often used in cancer therapy, such as etoposide [7,8] (see Section 3.3). A non-canonical pathway (recently reported) in which AMPK is activated by direct binding of long-chain fatty acyl-CoA esters (see Section 4.3). There are already indications for different targets being modified depending on whether AMPK is activated by the lysosomal pathway (#2 above) or by the canonical pathway in the cytoplasm (#1 above) [10], while acetyl-CoA carboxylase (ACC, one of the classical targets [11] that is a widely-used marker for AMPK activation) is not phosphorylated in response to the DNA damage pathway (#4 above), presumably because ACC is not present within the nucleus [7]
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