Novel insights on cellular suicide could provide new avenues for cancer therapies

Date:
November 12, 2020
Source:
University of California - Santa Barbara
Summary:
When it comes to complex life -- that of the multicellular variety
- - cell death can be just as important as survival. It allows
organisms to clean house and prevent the proliferation of damaged
cells that could compromise tissue function.



FULL STORY ==========================================================================
When it comes to complex life -- that of the multicellular variety --
cell death can be just as important as survival. It allows organisms to
clean house and prevent the proliferation of damaged cells that could compromise tissue function.


========================================================================== Several years ago, biologist Denise Montell, a distinguished professor
at UC Santa Barbara, found that sometimes cells survive after what was considered the critical step in cellular suicide. Now, she and her lab
have identified two key factors involved in this remarkable recovery.

The findings, published in Nature Communications, indicate that this
survival mechanism may be critical to normal tissue recovery from extreme stress rather than a fluke occurrence. Understanding its nuances could
also provide new strategies for treating cancers.

Apoptosis is the most common way cells commit suicide, and this process
is critical in maintaining an organism's wellbeing. Living things need
a way to terminate cells when they are badly injured or their DNA is
damaged. Apoptosis is also part of natural turnover, especially in blood
cells, skin cells and the lining of the gut.

"Before our work, people really thought that apoptosis was
an all-or-nothing decision," said Montell, Duggan Professor in the
Department of Molecular, Cellular, and Developmental Biology. "You either committed to suicide and went through with it, or you didn't." Scientists considered the activation of an enzyme appropriately called "executioner caspase" to be the point of no return. This enzyme essentially slices
and dices many of the cell's proteins. But it turns out apoptosis is
more nuanced than previously known, and sometimes cells survive the
executioner caspase via another process -- anastasis.



==========================================================================
Back from the brink This phenomenon first came to Montell's attention
around 2010. Generally, scientists studying apoptosis use extreme
conditions that cause all the cells in their sample to die. A doctoral
student in her lab at the time was curious whether cells could survive
the activation of caspase if he removed the substance that induced
apoptosis. To everyone's surprise, many of them did.

Since then scientists have observed anastasis in cells from many different organisms, including humans, mice and fruit flies. Montell and her team
decided to search for genes that would either enhance or inhibit the
ability of cells to undergo this process.

To this end, the researchers applied a technique they developed in
2016. By breeding transgenic fruit flies that express a specific protein
that is cut by the executioner caspase, they initiated a series of
events that ultimately makes the cells fluoresce green. That permanently identifies any cell that has survived through this phase of apoptosis.

With this tool on hand, the team, led by former postdoctoral fellow
Gongping Sun, set out to identify the genes involved in anastasis. Given
they couldn't investigate all 13,000 genes in the fruit fly genome, the researchers combed their own data as well as the literature to identify candidate genes, eventually settling on about 200 to investigate further.



==========================================================================
Sun and her lab mates took hundreds of fruit flies and knocked out the expression of a different gene in half of the cells of each animal. This enabled them to control for other factors that might influence the
results.

In the paper published in 2016, the team found that some cells undergo anastasis during normal development of the fruit fly. In the new paper,
they therefore looked for changes in the percentage of cells that went
through this process during development. They also tested the genes for
their ability to affect anastasis in response to stresses like radiation
and heat.

Distinguishing between genes involved in anastasis and those that are
simply necessary for basic survival was a challenge. "Because if it's
necessary for survival, period, then it's also going to be necessary
for recovery from the brink of death," Montell said.

So, the team looked not only at how many cells in a sample fluoresced
green after the experiment, but the ratio of green cells to non-green
cells. If the gene in question was necessary for basic survival, but not involved in anastasis, it affects all cells equally. This would impact
the overall number of fluorescent cells, but leave the ratio unchanged.

The researchers found two proteins, and the genes that coded for them,
were instrumental in anastasis. The first, AKT1, is a well-studied and
renowned survival protein that is activated in response to growth factors, essentially telling the cell to grow and divide. Scientists were aware
that it can block the activation of executioner caspase, but the team discovered it can also make the difference between survival and death
after caspase has been triggered.

The other protein, CIZ1, is not as well-studied, and shows up in a number
of unrelated papers across the literature. In nearly all these instances
it appears that CIZ1 also promotes survival from stress. For instance,
a decreased amount of CIZ1 is associated with increased age-dependent neurodegeneration in mice.

The involvement of these two proteins in anastasis indicates that
it is probably a very ancient process. "Not just the phenomenon of
cells recovering from the brink of death, but even the mechanism --
the molecules involved - - are so deeply conserved in evolution that
flies and mice are using the same molecules," Montell said.

Apoptosis and fighting cancer These findings are a huge step forward
in understanding apoptosis on a fundamental level. They also suggest
possible applications -- especially in efforts to combat cancer.

Apoptosis serves an important function in maintaining stable equilibrium
within complex organisms. Under normal circumstances -- say UV damage
to a skin cell - - the body wants the injured cell to die so that it
doesn't develop into a condition like melanoma.

"However, if you were subjected to extreme stress you might not want
every cell to commit apoptosis," Montell said. "That might result in
permanent tissue damage from which it would be very hard to recover."
In response to severe but temporary trauma, it could be beneficial for
some of the cells to be able to bounce back. Montell suspects this is
the primary reason that organisms evolved a way to circumvent apoptosis.

The temporary nature of the stress seems to be the critical factor both
in the role anastasis plays in promoting healing and in the mechanism
itself. When a cell is under extreme stress, like radiation or chemical exposure, two things happen simultaneously: The cell activates the
apoptosis response -- including executioner caspase -- while also
activating pro-survival responses.

"It's like putting on the accelerator and the brake at the same time,"
Montell said.

The apoptotic factors reinforce themselves, so if the stressful conditions persist, the process crosses a threshold and the cell dies. But if the
stress is only transient, the pro-survival pathway is already poised to
kick in and help the cell recover. Researchers don't fully understand
how the cell turns off the apoptotic pathway, but proteins like AKT1
and CIZ1 are likely involved.

There is, however, a dark side to this survival mechanism. "Anastasis
could be a good thing if you're trying to repair a damaged tissue, but
it could be a bad thing in that it might promote the growth of tumors,"
Montell pointed out, "especially in response to chemotherapy and radiation treatments, which are extreme temporary stresses." This matches the
experience of many physicians, Montell explained. A lot of cancer
patients initially respond well to treatments; their tumors shrink
and their condition improves. But unfortunately, the tumors often grow
back. And scientists aren't certain why this is.

Some think the resurgence could be the result of drug-resistant cells
that exist in the tumor, which then seed the relapse. This paper provides another hypothesis -- "the idea that the treatment itself could induce
the cancer cells to undergo this stress-dependent survival process,"
Montell said.

This notion could fundamentally change the way doctors think about
preventing relapse. There isn't much you can do against drug-resistant
cells, Montell said, but if the relapse is due to this survival mechanism, these findings could inform new therapies.

Drugs that inhibit AKT1 are currently in clinical trials. These could
be combined with other therapies to increase their effectiveness,
potentially enabling doctors and researchers to inhibit anastasis in
cancer cells while promoting it normal cells.

What's more, successful cancer cells can actually induce apoptosis in
the T cells that the immune system sends to attack them, according to
Montell. This presents another target for anastasis therapies.

"There's this ongoing war between the immune system and cancer," Montell
said, "and if you can tip the balance even a little bit, you can start
to win."

========================================================================== Story Source: Materials provided by
University_of_California_-_Santa_Barbara. Original written by Harrison
Tasoff. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Gongping Sun, Xun Austin Ding, Yewubdar Argaw, Xiaoran Guo,
Denise J.

Montell. Akt1 and dCIZ1 promote cell survival from apoptotic caspase
activation during regeneration and oncogenic overgrowth. Nature
Communications, 2020; 11 (1) DOI: 10.1038/s41467-020-19068-2 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/11/201112165824.htm

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