To destroy cancer cells, team 'travels back in time'
Biologist reconstructs 650-million-year-old enzyme to understand
programmed cell death

Date:
January 12, 2022
Source:
University of Texas at Arlington
Summary:
When an individual suffers from cancer, the process of programmed
cell death called apoptosis does not occur normally, permitting
abnormal cells to thrive.



FULL STORY ==========================================================================
When an individual suffers from cancer, the process of programmed cell
death called apoptosis does not occur normally, permitting abnormal
cells to thrive.


==========================================================================
In a new study, Clay Clark, chair and professor of biology at The
University of Texas at Arlington, explores the ancestry of a class of
enzymes responsible for killing cells. These enzymes, known as effector caspases, provide insight into the process of cell death and how it can
be manipulated in disease states.

"If drug developers want to target a cancer cell, they could activate
the caspases to perform their normal function of killing cells," Clark
said. "But we first need to isolate the caspases of cancer cells and not
alter their activity in normal cells. The question is, how can we target
the activity of the tumor cell without disturbing its healthy neighbors."
The study, "Evolution of the folding landscape of effector caspases,"
appears in the Journal of Biological Chemistry. In it, Clark and co-author Suman Shrestha, UTA alumnus and postdoctoral fellow at Princess Margaret
Cancer Center, look to the past for answers.

Cells have had effector caspases since organisms called eukaryotes
emerged more than a billion years ago. Over time, the caspases evolved
from one to 12 proteins that serve various functions during cell growth
and division. To understand their evolution, Clark's laboratory used a computational method called ancestral state reconstruction to recreate
a 650-million-year-old protein sequence of an ascendant of caspases 3,
6 and 7.

Caspases are the central components of apoptosis. In cancerous states,
cells turn off caspases and circumvent the cell death process. A goal
of Clark's research is to understand how effector caspases work in
healthy conditions.

Once the proteins' normal function is understood, Clark's team could
discover methods to activate them in disease states to destroy abnormal
cells while preserving healthy ones.

By examining the ancestor's characteristics and tracing the protein's
evolution into multiple members, Clark's team discovered commonalities and differences among caspases 3, 6 and 7 that could allow for the isolated activation of proteins in tumor cells without disrupting the activity
of healthy cells.

Morteza Khaledi, dean of the College of Science, said the results of the
study will advance humanity's battle to mitigate the effects of cancer.

"By employing the innovative methods of ancestral state reconstruction,
Dr.

Clark's team has discovered vital information about the essential building blocks for healthy human bodies," Khaledi said. "The knowledge uncovered
in this study provides another weapon in our fight against cancer." ========================================================================== Story Source: Materials provided by
University_of_Texas_at_Arlington. Original written by Linsey
Retcofsky. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Suman Shrestha, A. Clay Clark. Evolution of the folding landscape of
effector caspases. Journal of Biological Chemistry, 2021; 297 (5):
101249 DOI: 10.1016/j.jbc.2021.101249 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/01/220112094022.htm
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