Posts Tagged ‘AMP-activated protein kinase’

AMPK Is a Negative Regulator of the Warburg Effect and Suppresses Tumor Growth In Vivo

Reporter-Curator: Stephen J. Williams, Ph.D.

There has been a causal link between alterations in cellular metabolism and the cancer phenotype.  Reorganization of cellular metabolism, marked by a shift from oxidative phosphorylation to aerobic glycolysis for cellular energy requirements (Warburg effect), is considered a hallmark of the transformed cell.  In addition, if tumors are to survive and grow, cancer cells need to adapt to environments high in metabolic stress and to avoid programmed cell death (apoptosis). Recently, a link between cancer growth and metabolism has been supported by the discovery that the LKB1/AMPK signaling pathway as a tumor suppressor axis[1].

LKB1/AMPK/mTOR Signaling Pathway

The Liver Kinase B1 (LKB1)/AMPK  AMP-activated protein kinase/mammalian Target of Rapamycin Complex 1 (mTORC1) signaling pathway links cellular metabolism and energy status to pathways involved in cell growth, proliferation, adaption to energy stress, and autophagy.  LKB1 is a master control for 14 other kinases including AMPK, a serine-threonine kinase which senses cellular AMP/ATP ratios.  In response to cellular starvation, AMPK is allosterically activated by AMP, leading to activation of ATP-generating pathways like fatty acid oxidation and blocking anabolic pathways, like lipid and cholesterol synthesis (which consume ATP).  In addition, AMPK regulates cell growth, proliferation, and autophagy by regulating the mTOR pathway.  AMPK activates the tuberous sclerosis complex 1/2, which ultimately inhibits mTORC1 activity and inhibits protein translation.  This mTOR activity is dis-regulated in many cancers.

LKB1AMPK pathway

LKB1/AMPK in Cancer

  • Somatic mutations of the STK11 gene encoding LKB1 are detected in lung and cervical cancers
  • Therefore LKB1 may be a strong tumor suppressor
  • Pharmacologic activation of LKB1/AMPK with metformin can suppress cancer cell growth

In a recent Cell Metabolism paper[2], Brandon Faubert and colleagues describe how AMPK activity reduces aerobic glycolysis and tumor proliferation while loss of AMPK activity promotes tumor proliferation by shifting cells to aerobic glycolysis and increasing anabolic pathways in a HIF1-dependent manner.

The paper’s major findings were as follows:

  • Loss of AMPKα1 cooperates with the Myc oncogene to accelerate lymphomagenesis
  • AMPKα dysfunction enhances aerobic glycolysis (Warburg effect)
  • Inhibiting HIF-1α reverses the metabolic effects of AMPKα loss
  • HIF-1α mediates the growth advantage of tumors with reduced AMPK signaling


AMPK is a metabolic sensor that helps maintain cellular energy homeostasis. Despite evidence linking AMPK with tumor suppressor functions, the role of AMPK in tumorigenesis and tumor metabolism is unknown. Here we show that AMPK negatively regulates aerobic glycolysis (the Warburg effect) in cancer cells and suppresses tumor growth in vivo. Genetic ablation of the α1 catalytic subunit of AMPK accelerates Myc-induced lymphomagenesis. Inactivation of AMPKα in both transformed and nontransformed cells promotes a metabolic shift to aerobic glycolysis, increased allocation of glucose carbon into lipids, and biomass accumulation. These metabolic effects require normoxic stabilization of the hypoxia-inducible factor-1α (HIF-1α), as silencing HIF-1α reverses the shift to aerobic glycolysis and the biosynthetic and proliferative advantages conferred by reduced AMPKα signaling. Together our findings suggest that AMPK activity opposes tumor development and that its loss fosters tumor progression in part by regulating cellular metabolic pathways that support cell growth and proliferation.

Below is the graphical abstract of this paper.

Graphical Abstract FINAL.pptx

(Photo credit reference(2; Faubert et. al) permission from Elsevier)

However, this regulation of tumor promotion by AMPK may be more complicated and dependent on the cellular environment.

Nissam Hay from the University of Illinois College of Medicine, Chicago, Illinois, USA and his co-workers Sang-Min Jeon and Navdeep Chandel were investigating the mechanism through which LKB1/AMPK regulate the balance between cancer cell growth and apoptosis under energy stress[3]. In their system, the loss of function of either of these proteins makes cells more sensitive to apoptosis in low glucose environments, and cells deficient in either AMPK or LKB1 were shown to be resistant to oncogenic transformation.  Whereas previous studies showed (as above) AMPK opposes tumor proliferation in a HIF1-dependent manner, their results showed AMPK could promote tumor cell survival during periods of low glucose or altered redox status.

The researchers incubated LKB1-deficient cancer cells in the presence of either glucose or one of the non-metabolizable glucose analogues 2-deoxyglucose (2DG) and 5-thioglucose (5TG), and found that 2DG, but not 5TG, induced the activation of AMPK and protected the cells from apoptosis, even in cells that were deficient in LKB1.

The authors demonstrated that glucose deprivation depleted NADPH levels, increased H2O2 levels and increased cell death, and that this was accelerated in cells deficient in the enzyme glucose-6-phosphate dehydrogenase. Anti-oxidants were also found to inhibit cell death in cells deficient in either AMPK or LKB1.

Knockdown or knockout of either LKB1 or AMPK in cancer cells significantly increased levels of H2O2 but not of peroxide (O2) during glucose depletion. The glucose analogue 2DG was able to activate AMPK and maintain high levels of NADPH and low levels of H2O2 in these cells.

The nucleotide coenzyme NADPH is generated in the pentose phosphate pathway and mitochondrial metabolism, and consumed in H2O2 elimination and fatty acid synthesis. If glucose is limited mitochondrial metabolism becomes the major source of NADPH, supported by fatty acid oxidation. AMPK is known to be a regulator of fatty acid metabolism through inhibition of two acetyl-CoA carboxylases, ACC1 and ACC2.

Short interfering RNAs (siRNAs) to knock down levels of both ACC1 and ACC2 in A549 cancer cells and found that only ACC2 knockdown significantly increased peroxide accumulation and apoptosis, while over-expression of mutant ACC1 and ACC2 in LKB1-proficient cells increased H2O2 and apoptosis.

Therefore, it was concluded AMPK acts to promote early tumor growth and prevent apoptosis in conditions of energy stress through inhibiting acetyl-CoA carboxylase activity, thus maintaining NADPH levels and preventing the build-up of peroxide in glucose-deficient conditions.

This may appear to be conflicting with the previous report in this post however, it is possible that these reports reflect differences in the way cells respond to various cellular stresses, be it hypoxia, glucose deprivation, or changes in redox status.  Therefore a complex situation may arise:

  • AMPK promotes tumor progression under glucose starvation
  • AMPK can oppose tumor proliferation under a normoxic, HIF1-dependent manner
  • Could AMPK regulation be different in cancer stem cells vs. non-stem cell?


1.            Green AS, Chapuis N, Lacombe C, Mayeux P, Bouscary D, Tamburini J: LKB1/AMPK/mTOR signaling pathway in hematological malignancies: from metabolism to cancer cell biology. Cell Cycle 2011, 10(13):2115-2120.

2.            Faubert B, Boily G, Izreig S, Griss T, Samborska B, Dong Z, Dupuy F, Chambers C, Fuerth BJ, Viollet B et al: AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo. Cell metabolism 2013, 17(1):113-124.

3.            Jeon SM, Chandel NS, Hay N: AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress. Nature 2012, 485(7400):661-665.

 Other posts on this site related to Warburg Effect and Cancer include:


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Upending the cliché of muscleheads, scientists at the Laboratory of Neuroscience at the National Institute on Aging recently set out to examine whether changes in muscles prompted by exercise might subsequently affect and improve the brain’s ability to think.

Lab animals and people generally perform better on tests of cognition after several weeks of exercise training, and studies have shown that over time, running and other types of endurance exercise increase the number of neurons in portions of the brain devoted to memory and learning. But the mechanisms that underlie this process remain fairly mysterious. Do they start within the brain itself? Or do messages arrive from elsewhere in the body to jump-start the process?

The researchers were especially interested in the possibility that the action starts outside the brain – and specifically in the muscles. “We wondered whether peripheral triggers might be activating the cellular and molecular cascades in the brain that led to improvements in cognition,” says Henriette van Praag, the investigator at the National Institute on Aging who led the study.

Muscles are, of course, greatly influenced by exercise. Muscle cells respond to exercise by pumping out a variety of substances that result in larger, stronger muscles. Some of those compounds might be entering the bloodstream and traveling to the brain, Dr. van Praag says.

The problem is that exercise is such a complicated physiological stimulus that it’s very difficult to isolate which compounds are involved and what their effects might be. So she and her colleagues decided to study “fake” exercise instead, using two specialized drugs that had been tested several years ago by scientists at the Salk Institute in San Diego. The drugs had been shown to induce the same kinds of changes in sedentary animals’ muscles that exercise would cause, so that even though the mice didn’t exercise, they physiologically responded as if they had.

One of the drugs that they used, known as Aicar, increases the muscles’ output of AMPK, an enzyme that affects cellular energy and metabolism. Regular endurance exercise, like running or cycling, increases the muscles’ production of this enzyme. In the Salk experiments, Aicar enabled untrained mice to run 44 percent farther during treadmill tests than other, sedentary animals that hadn’t received the drug.

The second compound, GW1516, a cholesterol drug, also stimulates biochemical changes in muscle cells like those caused by endurance exercise. But in the Salk studies, it had amplified endurance primarily in animals that also ran, allowing them to run farther than another set of running mice that didn’t get the drug. But it hadn’t done much muscle-wise for animals that remained sedentary.

By using these drugs in unexercised animals under well-controlled conditions, the scientists from the National Institute on Aging sought to determine whether changes in muscles then initiated changes in the brain.

And as it turned out, muscles did affect the mind. After a week of receiving either of the two drugs (and not exercising), the mice performed significantly better on tests of memory and learning than control animals that had simply remained quiet in their cages. The effects were especially pronounced for the animals taking Aicar.

The results, published in the journal Learning and Memory, showed that the drugged animals’ brains also contained far more new neurons in brain areas central to learning and memory than the brains of the control mice, an effect found by microscopic examination.

Because the two drugs “don’t cross the blood-brain barrier much, if at all,” Dr. van Praag says, “we could be fairly confident that the changes we were seeing were related to an exercise-type reaction in the muscles” and not to brain responses to the drugs.

The message of this finding, she continues, is that “improvements in cognition” that follow exercise “would seem to involve changes throughout the body and not just in the brain.”

Although the exact process isn’t clear, Dr. van Praag speculates that some of the AMPK enzyme created during exercise enters the bloodstream and travels to the brain, setting off a series of new reactions there. factors improve hippocampal neurogenesis and spatial memory in mice

Tali Kobilo, Chunyan Yuan, and Henriette van Praag
Reporter: Prabodh Kandala, PhD

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