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Medical News Today: Cancer cells’ survival strategy defeated with new approach

Some cancers put up a fight against regular treatments such as chemotherapy or radiotherapy due to their various “strategies” for survival. But by manipulating cellular processes, scientists have now found a way of bypassing one of cancer’s self-preservation mechanisms.
concept illustration of cancer cell death
Recent research reveals how we may be able to bypass one of cancer’s survival strategies and trigger tumor cell death.

Autophagy — a term meaning “self-devouring” in Greek — is, normally, cells’ way of staying orderly and functional.

This is due to the fact that when autophagy is triggered, cells break down the elements that aren’t useful any longer and “recycle” material for reuse.

This process has been shown to have complex implications for cancer cells; sometimes it helps to destroy them, but at other times it helps them to thrive.

One way in which cancer cells use autophagy “in their own interest” is to evade apoptosis, or cell death.

Apoptosis and autophagy both rely on similar mechanisms to break down cellular material that is no longer helpful. But while apoptosis takes this disassembly all the way, eventually causing the cell to die, in autophagy, death is postponed by recycling some of the cellular material.

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In many cases, researchers have discovered that chemotherapy and radiotherapy can increase the presence of autophagy in cancer cells, which actually allows them to enter a “hiatus” mode that helps them to evade cell death and resume their activity later.

While researchers have studied the importance of autophagy inhibitors in promoting apoptosis, the underlying mechanisms that allow cell death to occur when this recycling process is inhibited have remained unclear.

Now, researchers from the University of Colorado Cancer Center in Aurora have begun to uncover some of these mechanisms, which has also allowed them to develop a fresh strategy to bypass tumor cells’ autophagy and trigger their death more efficiently.

The results of the study — which was led by Andrew Thorburn — have now been published in the journal Developmental Cell.

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Autophagy as ‘suspended animation’

In the new study, the researchers explain that the so-far mysterious link between autophagy and apoptosis is transcription factor FOXO3a, which is a protein that carries with it “instructions” as to what should take place at cellular level.

“The problem,” says Thorburn, “is this: many anti-cancer treatments push cancer cells to the brink of death. But the cells use autophagy to go into a kind of suspended animation, pausing but not dying.”

We don’t want cancer cells to pause; we want them to die. We show that FOXO3a may make the difference between these two outcomes.”

Andrew Thorburn

It turns out that FOXO3a plays a key role in the cellular homeostasis related to autophagy — that is, it helps to regulate that process. Interestingly, though, autophagy also helps to regulate the levels of this transcription factor.

In other words, when the presence of autophagy is increased, FOXO3a levels go down, and when autophagy is downregulated, more FOXO3a is produced, thereby boosting the cellular recycling process. This means that autophagy remains at constant levels, sometimes despite the action of chemotherapy drugs.

Previous research carried out at Thorburn’s laboratory revealed that another protein — known as PUMA — is key in “telling” cells when to self-destruct. Now, Thorburn and team have also found that FOXO3a can increase the expression of the gene that drives the production of PUMA.

Long story short, when autophagy is inhibited, more FOXO3a is produced, and when that happens, the heightened levels of FOXO3a help boost the presence of autophagy in cancer cells again. But at the same time, the transcription factor increases the presence of PUMA, which drives cell death.

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Mechanism suggests combination therapy

Following these discoveries, the scientists were interested in seeing whether they could use these mechanisms to render cancer cells more vulnerable to apoptosis. Their strategy involved using autophagy inhibitors alongside a tumor suppressing drug called Nutlin.

While the drug is known to stunt the growth of cancer cells, it had not been tied to triggering cell death. So, the researchers wanted to learn whether, by pairing it up with autophagy inhibitors, apoptosis would be prompted more efficiently.

The reason why Thorburn and colleagues decided to test both therapies in concert is because both autophagy inhibition and Nutlin are known to increase the production of PUMA, though they do so through independent channels: FOXO3a and a transcription factor known as p53, respectively.

“What we wanted to see,” says first author Brent Fitzwalter, “is whether these two things together — Nutlin along with autophagy inhibition — would increase PUMA past the point of growth inhibition and into actual cell death.”

After analyzing a series of tests conducted on cell cultures and mouse models of cancer tumors, the researchers were delighted to see that this strategy did work the way they hoped it would.

The [result] was that we turned a drug that could slow down tumor growth but couldn’t kill cancer cells into one that now kills the cells.”

Andrew Thorburn

These findings, the researchers add, could provide the groundwork for future clinical trials putting this combination treatment to the test to confirm its effect.

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