Understanding how cells die is key to developing new treatments for many diseases, whether the goal is to kill cancer cells or to keep healthy cells alive in the face of other diseases, such as massive infections or stroke. Two new studies from Washington University School of Medicine in St. Louis have identified a previously unknown cell death pathway – called lysoptosis – and demonstrate how it could lead to new therapies for cervical cancer. ‘uterus.

The two studies, which together analyzed data from roundworms, mice and human cells, appear Jan. 12 in the journal Nature. Communications biology.

The blood of patients with cervical cancer and other types of tumors is studded with a protein called SERPINB3. According to the new research, when the gene that makes SERPINB3 is missing from cervical cancer cells, the tumor cells die more easily when exposed to radiation stress. Similarly, the microscopic roundworms called C.elegans lacking the equivalent gene die more easily when exposed to stresses in their environment.

“It has long been known that high levels of this protein in the blood are a marker for cervical cancer and other squamous cell cancers – the higher the protein levels in the blood, the worse the prognosis” , said Stephanie Markovina, MD, PhD, assistant professor of radiation oncology.

“We wondered if this protein could do anything to protect against cancer. We thought it was possible that the gene protected cancer cells from stress in the same way that the roundworm equivalent gene protected C.elegans stress.

Markovina collaborated with Gary Silverman, MD, PhD, Harriet B. Spoehrer Professor and Chief of the Department of Pediatrics; and Cliff J. Luke, PhD, associate professor of pediatrics, who had studied this pathway in C.elegans and smile.

“One day I noticed that the worms that had the equivalent gene knocked out were all dying,” Luke said. “I realized that instead of putting the roundworms in the normal saline solution – or salt water – that we used, I accidentally put them in plain water. The normal roundworms were just fine, but worms lacking the worm equivalent of the human SERPINB3 gene all dead. 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 mouse intestinal epithelial cells were more sensitive to stress when they lacked the mouse equivalent of the human. SERPINB3.”

In all cases – roundworms, mice and cervical cancer – the researchers found that this particular mode of cell death is triggered in a specific compartment of the cell called the lysosome, an important waste management center responsible for recycling. or elimination of cellular waste. The researchers found that these genes – called serpin genes – that protect against lysosome-triggered cell death (lysoptosis) and the cell death pathway itself are conserved in all species, from roundworms to humans.

“There are many different cell death pathways, and understanding the specific pathways involved in each individual pathway is vital to disease treatment,” said Silverman, also a professor of cell biology and physiology, and genetics, and director. executive of the Children’s Discovery Institute at Washington University School of Medicine and St. Louis Children’s Hospital. “The lysosome contains some of the most powerful enzymes in the body. If the lysosomes leaked a little, they could cause immeasurable damage to the cell. For this reason, most researchers have dismissed their role in cell death as their effect would be catastrophic. It was assumed that cells must have multiple protections to prevent this process from occurring.

“Our work shows that is not the case,” he said. “Lysosomes kinda leak all the time, and proteins like SERPINB3 are there to neutralize those enzymes if they leak out of the lysosome. When SERPINB3 levels are low or absent, or when stress is strong enough to cause a large lysosomal leak, cells die rapidly, being ravaged by lysosomal enzymes. The cells appear to explode and spit their contents into the extracellular space, where this triggers an intense inflammatory response. Thus, lysoptosis signifies an active and autonomous cell death process which significantly destroys the cell. This process is very different from apoptosis, in which the cell quietly implodes and cellular debris is cleaned up by neighboring cells.

To study the effects of SERPINB3 gene, Markovina used CRISPR gene-editing technology to delete the gene from cervical cancer cells. The researchers observed that cervical cancer cells implanted in mice were more sensitive to the stress of chemotherapy and radiation when they lacked this protective gene.

Researchers are screening experimental or Food and Drug Administration-approved drugs for other diseases to identify compounds that stop the SERPINB3 gene in cervical cancer cells, so that they can be killed – by lysoptosis – more easily with chemotherapy and radiotherapy.

“As soon as we have a drug candidate, we hope to get it into clinical trials as soon as possible,” said Markovina, who treats patients with gynecological cancers at the Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School. of Medicine.

Luke also pointed to situations in which a different treatment that prevents this type of cell death may be beneficial, including in viral or bacterial infections.

“We are also looking at drugs for potential therapies that would enhance the cellular protection this gene confers,” Luke said. “For example, premature babies have a high risk of developing a devastating inflammatory disease called necrotizing enterocolitis, in which cells in the inner lining of the intestine die. In this case, we would be interested in finding ways to increase the expression of SERPINB3 to protect against cell death in the gut.

Silverman added: “Evidence suggests that lysoptosis is how cells die after a massive injury, like a heart attack or stroke, or in highly inflammatory conditions like inflammatory bowel disease or enterocolitis. necrotizing. In some cases we would want to manipulate lysoptosis to help kill tumor cells, and in others we would want to block it when triggered inappropriately. We hope that this new knowledge can lead to new therapies for diseases in which this type of cell death plays a key role.


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