A team led by professor of biology, senior vice president of research at NYU Abu Dhabi and UAE national Sehamuddin Galadari, have discovered a new structural modification of AMP-activated protein kinase (AMPK) during anticancer therapy that could pave the way for development. of More Effective Cancer Treatments
AMPK normally functions as the cellular energy sensor that is activated when there is a shortage of energy in the body. Once activated, AMPK initiates events in the cell that restore energy balance. The main component of AMPK exists as two isoforms (functionally similar proteins): AMPK-⍺1 and AMPK-⍺2.
In an article entitled Caspase cleavage and AMPK-α1 energy sensor nuclear retention during apoptosis in Cell Reports, the research team identified that the enzyme caspase-3 cleaves specifically AMPK-α1 (but no -⍺2) during cancer treatment. Scientists also identified the precise location of the truncation, the process of shortening something by removing part of it, and found that, as a result, the cleaved AMPK-⍺1 is trapped in the cell nucleus.
The findings are of significant clinical and biological significance because they will help researchers design and develop a drug that specifically targets the cleaved AMPK-⍺1 cleaved within the nucleus, which could increase the effectiveness of existing chemotherapy or radiation therapy.
Despite advances in biomedical research and clinical applications, cancer remains one of the leading causes of death worldwide. Most anticancer drugs act to induce death in cancer cells. However, resistance to therapy remains the main limiting factor in achieving cancer care. In our work based on cell culture models, we observed that the cleaved AMPK-⍺1 retained in the nucleus confers protection against cell death induced by anticancer drugs, causing resistance to chemotherapy. “
Sehamuddin Galadari, Professor of Biology, Senior Vice President for Research at NYU Abu Dhabi
The study was conducted in collaboration with Professor Grahame Hardie of the University of Dundee School of Life Sciences. Hardie, a pioneer in AMPK research, discovered and defined AMPK in the 1980s and characterized several of its functions.
NYUAD researcher and lead author Faisal Thayyullathil commented: “Interestingly, the gene encoding AMPK-α1 is frequently amplified in human cancers. Our results suggest that genomic instability in these tumors could precipitate rupture. of caspase and amplified AMPK-α1 nuclear retention, thus protecting tumor cells from cell death. “
NYUAD researcher and lead author Anees Rahman added: “Improving our understanding of the specific functions of the cleaved AMPK-α1 compartment will help us develop strategies to optimize the clinical outcome of therapeutic interventions.” .
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Magazine reference:
Cheratta, AR, et al. (2022) Caspase cleavage and nuclear retention of the AMPK-a1 energy sensor during apoptosis. Cell reports. doi.org/10.1016/j.celrep.2022.110761.