Fatty acid triggers newfound form of cell death in cancer
Through experiments on roundworms and human cells in the lab, scientists have found a potential new pathway for the treatment of cancer that involves a naturally occurring fatty acid. By subjecting cancer cells to this new foe, the team was able to kill them off through a recently discovered mechanism known as ferroptosis, a type of programmed cell death that could also have ramifications for diseases other than cancer.
The research was carried out at Washington State University (WSU) and centers on the polyunsaturated fatty acid known as dihomogamma-linolenic acid, or DGLA. While it can be found naturally in small quantities in the human body, DGLA doesn’t feature heavily as part of our diet, which means its effects aren’t as well understood as those of some other fatty acids.
Leader of the research Jennifer Watts had actually been investigating DGLA as part of her wider research into dietary fats for almost two decades. A key part of this is Caenorhabditis elegans, a nematode that features as an animal model in all kinds of scientific research, from the study of bone loss in astronauts to the discovery of brain hormones that trigger fat burning in the gut.
The researchers began by feeding C. elegans a diet of bacteria-carrying DGLA, which served to kill off all of the worms’ germ cells, along with the stem cells that create them. Watching this process play out, the team observed many signs of ferroptosis, a kind of cell death associated with an accumulation of iron and lipid peroxides in the cell.
This is a type of cell death that has only came to light in recent years, but one that is already being linked to a range of conditions including diseases of the blood, the nervous system and kidney injuries. Back in March we looked at molecule discovered by an MIT and Harvard team that could trigger ferroptosis to kill off cancer cells, potentially opening up a new class of drugs. The WSU team had reason to suspect that DGLA could serve as another trigger.
"Many of the mechanisms we saw in the nematodes were consistent with the hallmarks of ferroptosis in mammalian systems, including the presence of redox-active iron and the inability to repair oxidized lipids, which are like molecular executioners," says Marcos Perez, a WSU doctoral student and first author on the paper.
To explore how DGLA might drive ferroptosis in people, the team subjected human cancer cells to the fatty acid in the lab. Through these experiments the team demonstrated that it could indeed induce ferroptosis in human cancer cells, and found that by removing other fatty acids called ether lipids that appear to protect against it, they could kill off the cells with even greater efficiency.
"If you could deliver DGLA precisely to a cancer cell, it could promote ferroptosis and lead to tumor cell death," Watts says. "Also, just knowing that this fat promotes ferroptosis might also affect how we think about conditions such as kidney disease and neurodegeneration where we want to prevent this type of cell death."
The team now plans to further explore DGLA and how it can trigger ferroptosis, with a particular focus on what role mitochondria, known as the power houses of calls, might play in process.
The research was published in the journal Developmental Cell.