Scientists have discovered a way to fight the overexpression of a protein associated with the growth of breast cancer.
They say pioglitazone, a drug that is typically used to treat type 2 diabetes, may offer a way to dial down levels of the protein NAF-1 and the activity of the iron-sulfur clusters it transports.
Further, the findings show that a single mutation to NAF-1 almost completely blocks the ability of cancer cells to proliferate, a result that supports the idea that lowering NAF-1 expression can help stop tumors.
Fine-tuning the drug to specifically address tumors could bring a new weapon to the battle against breast cancer and other cancers, researchers say. Overexpression of NAF-1 also has been associated with prostate, gastric, cervical, liver, and laryngeal cancer.
Overexpression Of NAF-1
NAF-1 is a member of the NEET family of proteins, which transport clusters of iron and sulfur molecules inside cells. They naturally adhere to the outer surface of the mitochondria, the “power plant” that supplies cells with chemical energy.
Experiments show that the overexpression of NAF-1 in breast cancer tumors enhances cancer cells’ ability to tolerate oxidative stress. That enhancement allows the tumors to become much larger and more aggressive, says Ron Mittler, professor of biological sciences at the University of North Texas.
“Now that we know tumors that overexpress this protein are more sensitive to this type of drug, we can design new drugs in a way that will attack the clusters,” he says.
Patricia Jennings, a professor of chemistry and biochemistry at the University of California, San Diego, says NAF-1:
“is kind of like a seesaw. It’s a sensor that tells your cells when they’re getting out of balance and works very hard to bring them back. But once they get a little too far out of balance, the cells can die.”
Stabilize The Cluster
Treating the tumors with pioglitazone stabilized the iron-sulfur clusters in NAF-1, reducing the tumors’ tolerance to oxidation.
“We now have examples of five or six different types of tumors that need this protein to proliferate,” Mittler says. “If they don’t have it, they die.”
The researchers also discovered that expression of an NAF-1 protein that carried a single-point mutation had a similarly toxic effect on cancer cells and prevented tumor proliferation.
Tumors depend on the lability, or the transient nature, of the clusters, says coauthor Rachel Nechushtai, professor at the Hebrew University of Jerusalem.
“The more NAF-1 you make, and the more its clusters can be transferred, the bigger the tumor develops.
We knew from previous studies that pioglitazone stabilizes the cluster. With the mutant, we hardly got any tumors and didn’t see angiogenesis (the process through which new blood vessels form). When we did see tumors, they were white, not red, because they had no blood vessels.
We thought, ‘How do we connect this to the clinics?’ The only connection was to try a drug that, like the mutation, also stabilizes the cluster. Fang (Bai, a postdoc at Rice University) showed in her simulations where the binding site is and why the drug stabilizes the cluster.”
José Onuchic, professor of physics and astronomy at Rice, whose lab specializes in predicting protein folding pathways through computer modeling, said:
“This is where the initial results from Fang are very nice, because she can show exactly how to modify the drug. That way, one can computationally design the drug before trying to make the real drug. It’s a much less expensive way to come up with possibilities.
We can design selective drugs that only bind to NAF-1 and not to other proteins to reduce the side effects based on our new method,” Bai adds.
The study was funded by Israel Science Foundation, the University of North Texas College of Arts and Sciences, the Israel Cancer Research Fund, the National Science Foundation, the Cancer Prevention and Research Institute of Texas, the Keck Center for Interdisciplinary Bioscience Training of the Gulf Coast Consortia, the Welch Foundation, and the National Institutes of Health.
Merav Darash-Yahana, et al Breast cancer tumorigenicity is dependent on high expression levels of NAF-1 and the lability of its Fe-S clusters PNAS; September 12, 2016, doi: 10.1073/pnas.1612736113