Study Uncovers New Mechanism Cells Use to Escape Death

Researchers in Germany have discovered a new mechanism by which cells stressed by free radicals manage to escape death—findings that could have implications for development and administration of cancer therapies.  

Cells die of ferroptosis when free radicals destroy their protective cell membrane in a chain reaction. Healthy cells are occasionally affected when they come under oxidative stress, but cancer cells are particularly susceptible to ferroptosis due to their active metabolism. However, researchers have been unable to explain how many malignant cells manage to escape this fate. Considerable efforts have been made to identify factors that make a cell susceptible or resistant to ferroptosis in the hopes of inducing cell death for therapeutic purposes. 

A recent study led by Tobias Dick at the German Cancer Research Center has discovered a new, unexpected mechanism by which cells protect themselves from ferroptosis. The findings center on persulfides, small molecules characterized by a group of two sulfur atoms and one hydrogen atom. Although science has only recently learned that persulfides can be produced by the human body—from the sulfur-containing amino acid cysteine—determining their significance and function has been elusive.

The new work is the first to indicate that cells use persulfides to protect themselves. Coauthor Uladzimir Barayeu, also of the German Cancer Research Center, observed that cells boost their production of persulfides as soon as they are stressed by radicals and are at risk of ferroptotic cell death. The team also determined that persulfides are highly efficient radical scavengers, interrupting the destructive chain reaction that threatens the integrity of cell membranes.

They also describe persulfides’ unusual mechanism for protection. When a persulfide encounters a free radical, it takes on its radical character, thus becoming a radical itself. But the new radical behaves in an unusual way—unlike other radicals, it is extremely inert and incapable of causing damage. It reacts exclusively with itself and produces more persulfides in a subsequent reaction. This means that persulfides hardly consume themselves in the elimination of free radicals, and even a very low concentration of persulfides can effectively eliminate a much higher concentration of radicals.

The scientists also showed that a cell's ferroptosis sensitivity depends on certain enzymes of sulfur metabolism that generate persulfides.

"Our new results could open up completely new starting points for attacking the internal resistance of cancer cells, for example by pharmacological inhibitors of the enzymes responsible for persulfide production," says Dick.

The findings were published recently in the journal Nature Chemical Biology.