New treatment target identified for radiation-resistant cervical cancer

Newswise – Understanding how cells die is essential for 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 the Washington University School of Medicine in St. Louis have identified a previously unrecognized cell death pathway – called lysoptosis – and demonstrate how it could lead to new therapies for cervical cancer.

The two studies, which together analyzed data on 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 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. Likewise, the microscopic roundworms called C. elegans those lacking the equivalent gene die more easily when exposed to the stresses of 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 better the prognosis. bad, “said Stephanie Markovina, MD, PhD, assistant professor of radiation oncology.

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

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

“One day I noticed that the worms whose equivalent gene had been removed were all dying,” Luke said. “I realized that instead of putting the roundworms in the normal saline – or salt water – that we were using, I accidentally put them in plain water. Normal roundworms were fine, but worms lacking the human worm equivalent SERPINB3 gene all died. 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 human murine equivalent SERPINB3. “

In all cases – roundworms, mice, and cervical cancer – researchers have found that this particular mode of cell death is triggered in a specific compartment of the cell known as the lysosome, an important center of management. waste responsible for recycling or disposing of cellular waste. Researchers have 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 for the treatment of the disease,” said Silverman, also professor of cell biology and physiology, and genetics, and Executive Director 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 bit, they could cause immeasurable damage to the cell. For this reason, most researchers have ruled out their role in cell death because their effect would be catastrophic. It has been assumed that cells must have multiple protections to prevent this process from happening.

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

Researchers are looking at drugs that are experimental or already approved by the Food and Drug Administration 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 radiation therapy.

“As soon as we have a drug candidate, we hope to get it into clinical trials as soon as possible,” said Markovina, who treats gynecologic cancer patients at the Siteman Cancer Center at Barnes-Jewish Hospital 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 infants 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 compose the expression of SERPINB3 to protect against cell death in the intestine.

Silverman added, “Evidence suggests that lysoptosis is how cells die after massive injury, like heart attacks or strokes, or in highly inflammatory conditions like inflammatory bowel disease or necrotizing enterocolitis. 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 inappropriately triggered. 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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Luke CJ, Markovina S, et al. Lysoptosis is a cell death pathway conserved during evolution and moderated by intracellular serpins. Biology of communications. January 12, 2022.

This work was supported by National Institutes of Health (NIH) grant numbers R01DK104946, R01DK114047, R01DK118568, K08CA237822, and K08AI144033; Society for Pediatric Research Physician Scientist Award; and the American Society for Clinical Oncology (ASCO) Career Development Award; and the Children’s Discovery Institute of the St. Louis Children’s Hospital Foundation.

Wang S, Luke CJ, et al. SERPINB3 (SCCA1) inhibits cathepsin L and lysoptosis, protecting cervical cancer cells from radiochemotherapy. Biology of communications. January 12, 2022.

This work was supported by the Elsa U Pardee Foundation; an American Society for Clinical Oncology (ASCO) Career Development Award; an award for young professors from the American Society for Therapeutic Radiation Oncology (ASTRO); and the National Cancer Institute of the NIH, grant numbers K08CA237822 and K12 CA167540; Washington University Center for Cellular Imaging (WUCCI), supported by Washington University School of Medicine, Children’s Discovery Institute at the University of Washington, and St. Louis Children’s Hospital, grant CDI-CORE-2015-505 and CDI numbers -CORE-2019-813; and The Foundation for Barnes-Jewish Hospital, grant numbers 3770 and 4642.

The 1,700 physicians at the Washington University School of Medicine are also on the medical staff at Barnes-Jewish and St. Louis Children’s Hospitals. The School of Medicine is a leader in medical research, education, and patient care, and is among the top recipients of research funding from the National Institutes of Health (NIH). Through its affiliations with Barnes-Jewish and St. Louis Children’s Hospitals, the School of Medicine is linked with BJC HealthCare.

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