Autophagy & the Cancer Cell Survival Strategy

Sometimes regular treatments such as chemotherapy or radiotherapy can only do so much against some cancers due to the cancers’ different ways to thrive. However, scientists have found a way by manipulating cellular processes through bypass of one of cancer’s self-preservation mechanisms.

Autophagy, a term that means “self-devouring” in Greek, is commonly the cells’ way of staying functional and orderly. They stay this way due to the fact that when autophagy is triggered, cells break down the elements that are of no use and are then “recycled”. The process has shown some complex implications for cancer cells, sometimes it aids to eradicate them, but other times it only helps them to survive. This function allows Cancer cells to evade apoptosis, also known as cell death.

Autophagy and apoptosis both rely on similar methods to break down cellular material that is no longer useful or helpful. In autophagy, death is postponed by recycling some of the cellular material, while apoptosis takes this disassembly all the way, eventually causing death to the cell. Researchers have also discovered that in many cases, chemotherapy and radiotherapy can increase the abundance of autophagy in cancer cell. This enables them to enter a “hiatus” mode that helps them to evade cell death and resume their activity later.

Although studied, the significance of autophagy inhibitors in promoting the underlying mechanisms that enable cell death to happen have remained uncertain.

The researchers explain in this new study that the mysterious link between autophagy and apoptosis is transcription factor FOXO3a, a protein that carries with it “instructions” as to what should occur at cellular level.

However, it turns out that FOXO3a plays a vital role in the cellular homeostasis, helping regulate the process. Interestingly, though, it also aids in regulating the levels of this transcription factor. Simply put, FOXO3a levels go down when the presence of autophagy is increased. when autophagy is downregulated, more FOXO3a is created, thereby boosting the cellular recycling process. This means that despite the action of chemotherapy drugs, autophagy remains at constant levels

Another protein, also known as PUMA, was revealed after a previous research has been carried out at Thorburn’s laboratory. This protein is key in “telling” cells when to self-destruct. Heightened levels of FOXO3a help boost the presence of autophagy in cancer cells again when autophagy is inhibited. At the same time, cell death is driven by the transcription factor which increases the presence of PUMA.

Mechanism suggests combination therapy

Following these studies, the scientists were interested in seeing whether they could use these methods to render cancer cells more defenseless to apoptosis. Their strategy involved adding a tumor-suppression drug called Nutlin. 

Nutin is known to stunt the growth of cancer cells. However, it hasn’t been tied to triggering cell death. With this, researchers wanted to learn whether apoptosis would be prompted more efficiently by pairing it up with autophagy inhibitors. 

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