Researchers at the University of Texas MD Anderson Cancer Center have made an important discovery about how some cancers rely on glucose to survive which could lead to the development of tumor-specific treatments that do not affect healthy cells.
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The team describes how some cancer cells that have high expression of a certain amino acid transporter and effectively become “addicted” to glucose could be targeted with glucose transporter (GLUT) inhibitors.
The amino acid transporter is called solute carrier family 7 member 11 (SLC7A11) and examples of cancers that express this at high levels are lung cancer and kidney cancer renal cell carcinoma.
The study, which was recently published in the journal Nature Cell Biology aimed to find tumor-specific treatment approaches based on the metabolic reprogramming that cancer cells use to survive.
Study leader Boyi Gan from the university’s Department of Experimental Radiation Oncology says it is this metabolic reprograming that often results in cancer cells becoming extremely dependent on certain nutrients if they are going to have any chance of surviving.
"Limiting the supply of such nutrients or blocking their uptake or metabolism through pharmacological means may selectively kill 'addicted' cancer cells without affecting normal cells. Our understanding of nutrient dependency in cancer cells can provide great insights for targeting metabolic vulnerabilities in cancer therapies," says Gan.
The chemistry underlying cancer cell nutrient "addiction"
Gan gives an example of how this nutrient dependency can be used as a therapeutic approach in acute lymphoblastic leukemia.
This rare disease, which affects white blood cells is aggressive and quick to progress. It can affect adults and children, but it usually develops in children, adolescents, and young adults and is the most common form of leukemia among children. In the majority of cases, it affects children aged 0 to 5 years and is slightly more common among boys than among girls.
Unlike healthy cells, the cancer cells seen in acute lymphoblastic leukemia are unable to make the amino acid asparagine, a nonessential amino acid that is needed to synthesize glycoproteins and other proteins. Since the cancer cells cannot make this amino acid, they rely on extracellular sources for their survival. The treatment Gan describes disrupts this source of extracellular asparagine and once the cancer cells can no longer acquire this important amino acid, they die.
Another example of an amino acid cancer cells rely on is cystine – a protein component commonly found in eggs, meat and dairy products that is known to exert potent antioxidant activity.
The majority of cancer cells acquire cystine using the SLC7A11 amino acid transporter. Once the cancer cell has used the transporter to import cystine, it converts cystine into another amino acid called cysteine. This amino acid is used to produce and accumulate glutathione.
As an antioxidant, glutathione prevents essential cellular components from becoming damaged by reactive oxygen species Accumulating stocks of glutathione, therefore, help cancer cells to survive and it is the most abundant amino acid in the body.
"SLC7A11 is frequently overexpressed in cancers and has a well-established role in maintaining glutathione levels which reduce cancer cell death," says Gan.
Too much cystine can be toxic to cancer cells
However, Gan says the current study found that importing cystine actually poses a danger to cancer cells. Since it is one of the least soluble amino acids, an excess build-up of cystine inside cells can be toxic. Cancer cells, therefore, need to quickly change cystine into the related cysteine.
Consequently, cancer cells with high levels of SLC7A11 and high demand for cystine become dependent on glucose for survival.”
Boyi Gan, University of Texas MD Anderson Cancer Center
A promising new therapeutic approach
Gan and team, therefore, demonstrated a metabolic vulnerability among cancer cells that was associated with high levels of SLC7A11 expression – a finding that could pave the way for new therapeutic approaches.
The researchers found that using (GLUT) inhibitors to eliminate the glucose supply that cancer cells turn to, led cystine to accumulate inside the cells at a toxic level.
This strategy therefore specifically destroys cancer cells that are rich in SLC7A11 and suppresses tumor growth.
The findings suggest that GLUT inhibitors may represent a promising new approach to treating cancers such as lung and kidney cancer where tumors express high levels of the amino acid transporter SLC7A11.
New therapeutic strategies proposed for some lung and kidney cancers. EuerkAlert! 2020. Available at: https://www.eurekalert.org/emb_releases/2020-03/uotm-nts032620.php
Overview-Acute lymphoblastic leukaemia. NHS 2019. Available at: https://www.nhs.uk/conditions/acute-lymphoblastic-leukaemia/
Asparagine. PubChem. Available at: https://pubchem.ncbi.nlm.nih.gov/compound/asparagine