How Sugar Controls the Cancer-Causing NRF2 Protein

A study has identified the fact that sugar can regulate cancer-causing protein and help in developing a new treatment strategy. Gene mutations can cause many cancers. Among the mutated genes in cancer is the NRF2, which leads to lung, bladder, esophageal, head and neck and liver cancers. NRF2 helps to protect cells from reactive oxygen species, which are dangerous by-products from metabolism. Cancer cells use the NRF2 protein to safeguard their growth.

Scientists have been working on a drug that could block the action of NRF2, which for a long time, was considered undruggable.

The researchers discovered that:

  • Sugar molecules often attach to the NRF2 binding sites and shut it down. They have to be removed by an enzyme (fructosamine-3 kinase (FN3K)) before NRF2 acts. Since cancer cells depend on FN3K to remove the sugars from proteins, the enzyme can be used as a potential drug target.
  • The genome-editing tool CRISPR was used to identify the NRF2 key regulators. The scientists introduced mutations in NRF2 gene, which led to aggressive liver cancer. CRISPR was then used to introduce mutations across the genome to try and identify the changes that would prevent NRF2-driven liver cancers from growing.
  • When examining how FN3K affects NRF2, the researchers found that in those cells lacking the FN3K enzyme, the NRF2 protein was decorated with sugar molecules (glucose) which blocked the function of NRF2. The cancer cells that cannot eliminate these sugars die off.
  • Adding sugars (glycation) clearly affected the function of protein. It controlled the proteins in cancer cells, making it a potential treatment strategy that could be used to treat cancer.

This research has helped biologists to discover the possibilities of new treatments to cancer. If small molecules can inactivate FN3K, they will put NRF2 in a glycated and inactive state, thereby depriving cancer cells of their survival shield. If a drug would be developed to inactivate NRF2, then many cancer patients will be able to survive.

The research team is working to develop drugs that will inhibit FN3K pathways and improve cancer treatment.

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