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 illnesses, 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 January 12 in the Nature newspaper Communications Biology.
The blood of patients with cervical cancer and other types of tumors has a protein called SERPINB3. According to new research, when the gene that makes SERPINB3 is absent in cervical cancer cells, tumor cells die more easily when exposed to radiation stress. Similarly, microscopic roundworms called C. elegans that lack 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, Ph.D., assistant professor of radiation oncology.
“We wondered if this protein could do anything to protect cancer. We thought it was possible that the gene protects cancer cells from stress in the same way that the roundworm equivalent gene protected C. elegans from stress. stress.”
Markovina collaborated with Gary Silverman, MD, Ph.D., Harriet B. Spoehrer Professor and Chief of the Department of Pediatrics; and Cliff J. Luke, Ph.D., associate professor of pediatrics, who had studied this pathway in C. elegans and mice.
“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 quite correct, but the worms lacking the worm equivalent of the human SERPINB3 gene were all 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. As with C. elegans, we showed that mouse intestinal epithelial cells were more sensitive to stress when they lacked 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 in a specific compartment of the cell called the lysosome, an important waste management center responsible recycling or disposal of cellular waste. The researchers found that these genes, called serpin genes, which 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 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 It was assumed that cells must have multiple protections to prevent this process from happening.
“Our work shows that is not the case,” he said. “Lysosomes leak a little all the time, and proteins like SERPINB3 are there to neutralize these enzymes if they leak out of the lysosome. When SERPINB3 levels are low or absent, or when stress is strong enough to cause a big lysosomal leak , the 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, self-contained cell death process that destroys This process is dramatically different from apoptosis, in which the cell quietly implodes and cellular debris is scavenged by neighboring cells.
To study the effects of the 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 therapy when they lacked this protective gene.
Researchers are looking at experimental or Food and Drug Administration-approved drugs for other diseases to identify compounds that shut down the SERPINB3 gene in cervical cancer cells, so 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 Barnes-Jewish Hospital’s Siteman Cancer Center and Washington University School. of Medicine.
Luke also pointed out situations where 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 that this gene confers,” Luke said. “For example, premature babies are at 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 like to manipulate lysoptosis to help kill tumor cells, and in others, we would like to block it when it is 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.
Mechanism that alters the proliferation of cancer cells and induces their death
Cliff J. Luke et al, lysoptosis is an evolutionarily conserved cell death pathway moderated by intracellular serpins, Communications Biology (2022). DOI: 10.1038/s42003-021-02953-x
Songyan Wang et al, SERPINB3 (SCCA1) inhibits cathepsin L and lysoptosis, protecting cervical cancer cells from chemoradiation, Communications Biology (2022). DOI: 10.1038/s42003-021-02893-6
Provided by Washington University in St. Louis
Quote: New treatment target identified for radiation-resistant cervical cancer (January 12, 2022) Retrieved January 12, 2022 from https://phys.org/news/2022-01-treatment-radiation-resistant-cervical -cancer.html
This document is subject to copyright. Other than fair use for private study or research purposes, no part may be reproduced without written permission. The content is provided for information only.