Researchers at Sanford Burnham Prebys, led by Ze’ev Ronai, Ph.D., have shown for the first time that inhibiting a key metabolic enzyme selectively kills melanoma cells and stops tumor growth. Published in Nature Cell Biology, these findings could lead to a new class of drugs to selectively treat melanoma, the most severe form of skin cancer.
“We found that melanoma is addicted to an enzyme called GCDH,” says Ronai, professor and director of the NCI-designated Cancer Center at Sanford Burnham Prebys. “If we inhibit the enzyme, it leads to changes in a key protein, called NRF2, which acquires its ability to suppress cancer. Now, our goal is to find a drug, or drugs, that limit GCDH activity, potentially new therapeutics for melanoma.”
Because tumors grow rapidly and require lots of nutrition, researchers have been investigating ways to starve cancer cells. As promising as this approach may be, the results have been less than stellar. Denied one food source, cancers invariably find others.
GCDH, which stands for Glutaryl-CoA Dehydrogenase, plays a significant role in metabolizing lysine and tryptophan, amino acids that are essential for human health. When the Ronai lab began interrogating how melanoma cells generate energy from lysine, they found GCDH was mission-critical.
“Melanoma cells ‘eat’ lysine and tryptophan to produce energy,” says Sachin Verma, Ph.D., a postdoctoral researcher in the Ronai lab and first author of the study. “However, harnessing energy from this pathway requires cancer cells to quench toxic waste produced during this process. It’s a six-step process, and we thought the cells would need all six enzymes. But it turns out only one of these enzymes is crucial, GCDH. Melanoma cells cannot survive without the GCDH portion of the pathway.”
Further exploration showed that inhibiting GCDH in an animal model gave NRF2 cancer-suppressing properties.
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