A new study is suggesting that the protein NFS1 provides a central protection for cancer cells against oxygen and that it may be possible to leverage this discovery into a new lung cancer treatment. The results, reported online ahead of print on November 22nd in Nature, showed that lung adenocarcinoma cells survive an oxygen threat by producing more NFS1, which harvests sulfur from the amino acid cysteine to make iron-sulfur clusters.
“Cancer cells growing in cell culture exhibit vulnerabilities that are distinct from those growing in an animal as a tumor xenograft,” said lead study author Richard Possemato, PhD, an assistant professor in the Department of Pathology at NYU School of Medicine, New York, New York. “There are currently no drugs that readily target this liability. Hopefully this and similar work will spark the production of such drugs, which would provide a unique weapon in the armamentarium of anti-cancer treatments.”
Dr. Possemato and his colleagues focused on iron-sulfur cluster biosynthesis and the key enzyme NFS1, which initiates the synthesis of iron-sulfur cluster cofactors. Using mouse lung cancer xenograft models, they found that cancer cells growing in the lung exhibited an increased dependency on NFS1.
The research team used short hairpin RNAs to switch off 2,752 genes related to cell metabolism, including iron and sulfur biochemistry, one by one. They found that many genes which were essential to survival in high oxygen levels were not as important in low oxygen. However, the NFS1 gene was the most essential for survival at the elevated oxygen level present in the lungs, but not at the much lower oxygen level encountered by cells under the skin.
The researchers further found that when they treated cells in which NFS1 had been suppressed with pro-oxidants (tert-butyl hydroperoxide or inhibition of glutathione biosynthesis), cells underwent lysis and died without further inhibition of iron-sulfur cluster function. Possemato said the team discovered that these cells were dying by a recently described form of cell death termed ferroptosis, in which cell membrane lipids are oxidized. He and his team concluded that NFS1 suppression resulted in altered iron homeostasis, resulting in elevated free iron inside cancer cells.
“This is the first description of iron-sulfur cluster biosynthesis as a pathway that is altered in cancer, and the first description of a metabolic pathway whose dependence is related to the concentration of an extracellular metabolite. Moreover, suppression of NFS1 or activation of the downstream iron-starvation response provides an avenue to induce ferroptosis in cancer. As a metabolic enzyme, NFS1 should be readily druggable,” Possemato told OncoTherapy Network.