Completed Cancer Diabetes, Hormones & Metabolism

Role of AMPK in Nutrient Sensing and in Cancer

Funder Wellcome Charity-funded
Recipient organisation University of Dundee
Funding £1.3M
Period Oct 2017 — Oct 2022

In plain English

AI plain-English summary

Cells switch on a metabolic master switch called AMPK when glucose runs low—but the exact wiring of that switch has been unclear. This research tackles a fundamental gap in biology: how do human cells sense the availability of glucose, their primary fuel? The team has already discovered that AMPK detects falling levels of a sugar-processing molecule called fructose-1,6-bisphosphate, rather than directly measuring glucose itself. They now want to map the entire sensing chain—from the receptor protein aldolase through to AMPK—and understand how it adjusts the cell’s production of glycolytic enzymes. They will also screen for new chemical regulators of AMPK, test whether the enzyme acts as a sensor for the cell’s glycogen stores, and explore why different AMPK subunits are amplified or deleted in various human cancers. Because this is fundamental science, there is no immediate practical application. But the work could reshape our understanding of how cells balance energy supply and demand—a process that goes wrong in metabolic diseases, diabetes, and cancer. Deeper knowledge of AMPK’s sensing mechanisms may eventually point toward new drug targets, particularly for cancers that depend on altered glucose metabolism, or for improving chemotherapy with DNA-damaging drugs like etoposide.

View original technical description
Firstly, we will investigate the role of AMP-activated protein kinase (AMPK) in glucose sensing. Our recent work in collaboration with Shengcai Lin (Xiamen University) shows that mammalian AMPK is activated by glucose deprivation via a pathway independent of the canonical AMP/ADP-dependent pathway. AMPK appears instead to sense the levels of the glycolytic intermediate fructose-1,6-bisphosphate (FBP), with the effect being transmitted from the likely receptor, aldolase, to LKB1 and AMPK via LAMTOR1 and AXIN. We will investigate the possibility that this mechanism adjusts the levels of glycolytic enzymes according to glucose availability, via reciprocal regulation of AMPK and TORC1 at the lysosomal surface. Secondly, we will screen metabolites from animal cells to identify novel regulators of AMPK that bind the Allosteric Drug and Metabolite (ADaM) site. Thirdly, we will pursue our hypothesis that AMPK is a glycogen sensor that determines the final size of glycogen particles and also ensures that glycogen stores are rapidly replenished whenever they become depleted. Finally, we will investigate why some subunit isoforms of AMPK are amplified in human cancers, while others are either mutated or deleted, or unaffected. We will also investigate whether AMPK inhibitors might be useful adjuncts to chemotherapy with DNA-damaging drugs like etoposide.

View the original record at the funder ↗

Researchers

David Grahame Hardie (EPMC Awardee)

Related Research

Grants with similar aims, by meaning.

AMP-activated protein kinase - a tumour suppressor that opposes the metabolic changes in proliferating cells
Characterisation of TORC1 control of AMPK activity
Allosteric regulation of glycogen synthase in vivo and characterization and use of A-769662, a valuable tool for activation of AMP-activated protein kinase
The role of AMP-activated protein kinase in adipocyte glucose transport and insulin signalling
Investigation of an AMPK phosphatase

Original classification

Investigator Award in Science

Plain English summaries and category classifications on this site are generated by AI and may not perfectly reflect the original research.