It seems the worlds of the Walking Dead and science have somehow collided this week with the identification of so called “zombie” cells. No, this isn’t a form of cell that lumbers around feasting on the flesh of healthy cells (although let’s be honest, that would be pretty cool…) rather, this is the identification of a process that cancer cells may abuse in order to resurrect themselves back from the dead…

The Art of Autophagy

Cells have many strange and ingenious methods of surviving in dire situations. One of those mechanisms is called “autophagy”. Coming from the Greek words “auto” (self) and “phagein” (to eat), the process involves the destruction of intracellular materials in order to fuel cell survival. Usually, the process is reserved for the destruction of faulty or old proteins or organelles in order to fuel cell survival in situations of metabolic stress.

In cancer cells, this process can be hijacked, allowing tumour cells to survive in hostile environments such as those created by the introduction of anti-cancer agents, leading to cell resistance and tumour recurrence. The process therefore has attracted attention from scientists trying to establish a possible therapeutic target to prevent cancer cells from abusing this process.

Autophagy allows cells to degrade or "eat" its own contents in order to produce enough energy for cell survival in high stress environments.
Autophagy allows cells to degrade or “eat” its own contents in order to produce enough energy for cell survival in high stress environments.

The involvement of autophagy in cancer cell development and survival is not a new theory and has been an area investigated by scientists for quite some time now. However, this week a study was released expanding on this idea, introducing the notion of “zombie” cancer cells.

Cheating Death

The study put forward by the University of Colorado Cancer Center introduces the combination of autophagy with a second naturally occurring cell process – that of apoptosis.

Cell death tends to occur through two different means:

  1. NECROSIS – a process that tends to be the result of external injury to the cell, perhaps inferred by trauma or infection
  2. APOPTOSIS or “programmed cell death” – a process that is advantageous to the organism as a whole and is inferred through cellular signalling.

Apoptosis is one of the many methods for cells to prevent the formation of tumours by killing a faulty cell before it can ever divide and proliferate. The process itself is finely balanced; too much apoptosis can cause atrophy – the wasting away of a part of the body – whereas too little can lead to uncontrolled cell division. There are few mechanisms currently known that trigger apoptosis although the method in question in this study is the intrinsic apoptosis pathway.

A major organelle involved in apoptosis is the mitochondrion, an organelle that is also vital for maintaining correct cell metabolism. The intrinsic apoptosis pathway depends on the perforation of the mitochondrion outer membrane in order to release proteins that cause eventual cell breakdown. This process is called mitochondrial outer membrane permeabilisation or “MOMP“.

PUMA apoptosis
This is just one variation of the proposed method of cell survival through enhanced autophagy. An alternative theory suggests that autophagy of the released caspase proteins prevents any damage from occurring to the cell, giving the cell enough time to recover.

The processes of autophagy and apoptosis are intricately balanced to allow cells to survive enough in hostile environments but to die when thy are no longer needed. In a rather ingenious way of using the cells own defences against it, a cancer cell can tip the scales more in favour of autophagy meaning apoptosis is less likely to occur. In this study, a particular protein was identified as a potential indicator of this imbalance called p53 upregulated modulator of apoptosis or “PUMA“. The protein is governed by a higher gene called p53, a gene I have mentioned in past posts as a major contributor to tumour suppression.

In normal circumstances, PUMA is a pro-apoptotic protein that binds to an anti-apoptotic protein called Bcl-2. This study proposes that in the case of cancer cells, autophagy of PUMA leads to inefficient MOMP and therefore a slow apoptotic process. As the process is so slow, the cell can retain enough energy from autophagy to stop itself from dying and can eventually recover. An alternative notion proposed in past research suggests that it is autophagy of the caspase proteins themselves that prevents any damage from occurring to the tumour cell.

Below is a video that accompanies the report showing cells deficient in PUMA undergoing apoptosis due to the introduction of a therapeutic agent named TRAIL. Quickly after the cell is subjected to TRAIL, it rapidly shrinks following MOMP. However, rather than eventually fragmenting, the cell is seen to slowly recover, even dividing towards the end of the film.

Aim For The Head…

Although the idea of cancer cells being able to resurrect themselves may be frightening, the fact that it has been identified represents a huge development in the way that we can target resistant cells. If this were a report merely pointing out the fact that some cells can recover from dire situations then it would definitely be interesting, but wouldn’t tell us anything about how this process occurs. The identification of deficient PUMA levels as a potential driving force behind cell survival enables us to pinpoint exactly how the process can be reversed.

Therapies targeting apoptosis proteins have been considered for quite some time now, some in the form of stabilising therapies (in the case of faulty p53 proteins) and some focusing more on inhibiting individual proteins in the apoptosis signal pathways. From this study, it is clear that targeting PUMA in some form may well produce the desired effect of keeping a cancer cell dead. Perhaps by introducing a synthetic form of the protein (if that is at all possible), PUMA levels will be stable enough to counter-act a high occurrence of autophagy in cells. This may prove to be most effective in those cells that are lacking in or have a mutated version of the PUMA gene. Looking at the situation from a different perspective, it could be argued that targeting the autophagy process as a whole could produce the same effect of re-establishing normal PUMA levels, again resulting in a cancer cell staying dead.

All in all, the research is important for the field and brings light to another potential therapeutic target. As with all new targets though, whether it can be effectively targeted to make a difference is the real question. Unlike the undead, it’s never quite as easy as just aiming for the head.

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The “zombie” cells study: Thorburn, J et al. “Autophagy Controls the Kinetics and Extent of Mitochondrial Apoptosis by Regulating PUMA Levels” (2014) Cell Reports