New treatment target ID'd for radiation-resistant cervical cancer
Approach harnesses newly identified method of cell death

Date:
January 12, 2022
Source:
Washington University School of Medicine
Summary:
Understanding how cells die is key to developing new treatments for
many diseases, whether the goal is to make cancer cells die or keep
healthy cells alive in the face of other illnesses, such as massive
infections or strokes. Two new studies have identified a previously
unrecognized pathway of cell death -- named lysoptosis -- and
demonstrate how it could lead to new therapies for cervical cancer.



FULL STORY ========================================================================== Understanding how cells die is key to developing new treatments for many diseases, whether the goal is to make cancer cells die or keep healthy
cells alive in the face of other illnesses, such as massive infections
or strokes.

Two new studies from Washington University School of Medicine in
St. Louis have identified a previously unrecognized pathway of cell
death -- named lysoptosis -- and demonstrate how it could lead to new
therapies for cervical cancer.


==========================================================================
Both studies, which together analyzed data in roundworms, mice and human
cells, appear Jan. 12 in the Nature journal 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.

"It's been known for a long time that high levels of this protein in the
blood are a marker of cervical cancer and other squamous cell cancers --
the higher the protein levels in the blood, the worse the prognosis,"
said Stephanie Markovina, MD, PhD, an assistant professor of radiation oncology.

"We wondered if this protein may be doing something to protect the
cancer. We thought it was possible that the gene was protecting the
cancer cells from stress in the same way the equivalent roundworm gene
was protecting C. elegans from stress." Markovina collaborated with
Gary Silverman, MD, PhD, the Harriet B. Spoehrer Professor and head
of the Department of Pediatrics; and Cliff J. Luke, PhD, an associate
professor of pediatrics, who had been studying 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 -- or saltwater -- 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 in a specific compartment of the cell known
as the lysosome, an important waste-management center responsible for
recycling or disposing of cellular waste. The researchers discovered
that these genes -- called serpin genes -- that protect against cell
death triggered by the lysosome (lysoptosis) and the cell death pathway
itself are conserved across species, from roundworms to humans.

"There are many different cell death pathways, and understanding the
specific routes involved in each individual pathway is vital for the
treatment of disease," said Silverman, also a professor of cell biology & physiology, and of 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 lysosomes leaked a bit, they could do immeasurable harm to the cell. For
this reason, most investigators discounted their role in cell death
because their effect would be catastrophic. It was assumed that cells must
have multiple protections to prevent this process from ever happening.

"Our work shows that this is not the case," he said. "Lysosomes leak a
bit all the time, and proteins like SERPINB3 are there to neutralize these enzymes if they get out of the lysosome. When SERPINB3 levels are low or absent, or if the stress is strong enough to cause a big lysosomal leak,
the cells die quickly, ravaged by the lysosomal enzymes. The cells appear
to explode and spew their contents out into the extracellular space, where
it triggers an intense inflammatory response. So, lysoptosis signifies
an active, stand-alone cell death process that dramatically destroys the
cell. This process is very different from apoptosis, in which the cell
quietly implodes and the cell debris is cleaned by neighboring cells."
To study the effects of the SERPINB3 gene, Markovina used the gene editing technology CRISPR to delete the gene from cervical cancer cells. The researchers observed that cervical cancer cells implanted into mice were
more susceptible to the stress of chemotherapy and radiation when they
were missing this protective gene.



==========================================================================
The researchers are screening drugs that are either investigational or
already approved by the Food and Drug Administration 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 radiation.

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

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

"We're also screening drugs for potential therapies that would enhance
the cell 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 the
cells of the interior lining of the gut die off. In this case, we would
be interested in finding ways to dial up the expression of SERPINB3 to
protect against cell death in the gut." Added Silverman, "Evidence
suggests that lysoptosis is how cells die after massive injury, 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. We are hopeful this new knowledge can lead to novel
therapies for diseases in which this type of cell death plays a key role." ========================================================================== Story Source: Materials provided by
Washington_University_School_of_Medicine. Original written by Julia
Evangelou Strait. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Cliff J. Luke, Stephanie Markovina, Misty Good, Ira E. Wight,
Brian J.

Thomas, John M. Linneman, Wyatt E. Lanik, Olga Koroleva, Maggie R.

Coffman, Mark T. Miedel, Qingqing Gong, Arlise Andress, Marlene
Campos Guerrero, Songyan Wang, LiYun Chen, Wandy L. Beatty,
Kelsey N. Hausmann, Frances V. White, James A. J. Fitzpatrick,
Anthony Orvedahl, Stephen C.

Pak, Gary A. Silverman. Lysoptosis is an evolutionarily
conserved cell death pathway moderated by intracellular
serpins. Communications Biology, 2022; 5 (1) DOI:
10.1038/s42003-021-02953-x ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/01/220112121518.htm
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