Targeting NAF-1, a protein that is often overexpressed in breast cancers, may be key to stopping tumor growth, according to the results of a study published in the Proceedings of the National Academy of Sciences.
The study, “Breast cancer tumorigenicity is dependent on high expression levels of NAF-1 and the lability of its Fe-S clusters,” suggests that a drug typically used to treat type 2 diabetes, Actos (pioglitazone), may be able to halt the growth of breast cancers with high levels of the NAF-1 protein.
The NAF-1 protein is a member of the NEET family of proteins. These proteins contain clusters of iron-sulfur molecules and transport these clusters inside cells to help maintain the reduction-oxidation (redox) balance within cells.
In tumor cells, where metabolic activity is exceptionally high, the production of reactive oxygen species (ROS) is no surprise. Therefore, the cells have to come up ways to tolerate the elevated amount of ROS, which can be toxic and lead to cell death.
NAF-1 seems to be involved in that increased tolerance to ROS molecules; the researchers found that overexpressing the NAF-1 protein in breast cancer mouse models made the cancer cells more tolerant to oxidative stress, which allowed the tumors to become much larger and aggressive.
NAF-1 “is kind of like a seesaw,” Patricia Jennings, a Center for Theoretical Biological Physics affiliate and professor of chemistry and biochemistry at University of California, San Diego, said in a press release. “It’s a sensor that tells your cells when they’re getting out of balance and works very hard to bring them back.”
But the investigators found that a single mutation in NAF-1 that stabilized the iron-sulfur clusters and impaired their transference to other proteins reduced the ability tumor cells to deal with the high amount of oxidative stress.
“The more NAF-1 you make, and the more its clusters can be transferred, the bigger the tumor develops,” said Rachel Nechushtai, a study co-author and professor at Hebrew University in Jerusalem. With the mutation, this transference was not possible.
“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,” Nechushtai said.
The researchers knew from previous studies that Actos stabilizes the clusters in the NAF-1 proteins. And, similar to what had been observed in tumors with the NAF-1 mutation, Actos also reduces tumor cell tolerance to oxidation, so that the mice treated with Actos hardly developed any tumors. (Actos is FDA-approved, along with diet and exercise, to improve blood sugar control in adults with type 2 diabetes mellitus.)
“We now have examples of five or six different types of tumors that need this protein to proliferate,” said Ron Mittler, a professor of biological sciences at the University of North Texas. “If they don’t have it, they die.”
“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,” Mittler said.
Researchers believe that fine-tuning the drug to specifically target tumor cells may create a new weapon against breast and other cancers. One of the researchers involved, the postdoc Fang Bai from Rice University, was able to show where Actos binds in the NAF-1 protein and why it stabilizes the cluster, providing important information for further development of the drug.
“This is where the initial results from Fang are very nice, because she can show exactly how to modify the drug,” said José Onuchic, the Harry C. and Olga K. Wiess Chair of Physics and a professor of physics and astronomy at Rice, whose lab specializes in predicting protein folding pathways through computer modeling. “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 added.