New Cellular Death Pathway Identified

Two new studies from Washington University School of Medicine in St. Louis have identified a previously unrecognized pathway of cell death which they named lysoptosis. The studies, which together analyzed data in roundworms, mice and human cells, appear in Nature and Communications Biology.

The blood of patients with cervical cancer and other tumor types is dotted with a protein called SERPINB3. According to the new research, when the gene that manufactures SERPINB3 is absent in cervical cancer cells, the tumor cells die more easily when exposed to the stress of radiation. Similarly, microscopic roundworms called C. elegans that are missing the equivalent gene die more easily when exposed to stresses in their environments.

“One day I noticed that the worms that had the equivalent gene knocked out were all dying,” researcher Cliff Luke said. “I realized that instead of putting the roundworms in the normal saline that we used, I accidentally put them in regular water. The normal roundworms were totally fine, but the worms lacking the worm-equivalent of the human SERPINB3 gene all died. The plain water was a source of stress, and we determined that they lacked the gene that protects them from stress-induced cell death. We then wondered if this cell death was conserved in mammals. Similar to C. elegans, we showed that intestinal mouse epithelial cells were more sensitive to stress when missing the mouse equivalent of human SERPINB3.”

In all cases—roundworms, mice and cervical cancer—the researchers found that this particular mode of cell death is triggered by the lysosome. The researchers discovered that these genes, called serpin genes, that protect against this type of cell death trigger and the cell death pathway itself are conserved across species, from roundworms to humans.

 “Evidence suggests that lysoptosis is how cells die after massive injuries, such as from heart attacks or strokes, or in highly inflammatory conditions like inflammatory bowel disease or necrotizing enterocolitis. In some instances, we would want to manipulate lysoptosis to help kill tumor cells, and in others, we would want to block it when it is inappropriately triggered,” Collaborator Gary Silverman concluded. “We are hopeful this new knowledge can lead to novel therapies for diseases in which this type of cell death plays a key role.”