To be or not to be is the question faced by every cell in our body, and our health relies on it. All cells in the body are equipped with a self-destruct button and are happy to sacrifice themselves for the greater good, if circumstances require.
This process is called a programmed cell death, or ‘apoptosis’, and is an entirely normal function of a cell. A cell can choose to self-destruct and in this way protect neighbouring cells, if its vital functions are compromised, for example, if its DNA has been severely damaged. The self-destruction process is highly controlled to make sure that only the cells that are beyond rescue die. Cancer cells, however, can learn how to avoid programmed cell death, which helps them grow in harsh conditions and resist treatment. But can researchers outsmart them?
Internal alarm system
In our body, it’s estimated that around one million cells die every second as part of normal turnover when old cells are replaced with new ones. But programmed cell death can also act as an alarm system – it can alert our immune system that something bad is happening with the cell. If a cell becomes infected with a virus, it would choose to die pre-emptively, before the virus has a chance to multiply and infect neighbouring cells. The dying cell alerts the immune system by releasing special molecules, called DAMPs, that stimulate immune cells.
This process is also called an immunogenic cell death. Finding ways to convince cancer cells to commit immunogenic self-destruction would be extremely useful for treating the disease, as it could have a dual effect: killing cancer cells directly and activating the immune system to attack them.
A balancing act
A number of different proteins in the cell influence its decision to self-destruct. Some of them are pro-apoptotic, telling the cell to die, while others are anti-apoptotic, convincing the cell to choose life. The balance between these two groups of proteins inside the cell defines the cell’s fate. However, this decision doesn’t only rely on what’s happening inside the cell. It’s also influenced by the signals a cell receives from its environment and neighbours.
One set of proteins which play a role in blocking cell death are known as ‘inhibitor of apoptosis proteins’, or IAPs for short. These proteins are commonly found at higher levels than usual in cancer cells, helping them to resist treatments.
Since avoiding cell death is a hallmark of all types of cancer, researchers have been looking for ways to disrupt it in the search for better treatments. And excitingly, they believe that interfering with the action of IAPs in cancer cells could push them back towards ‘the cliff edge of death’, and make cancers more susceptible to existing treatments.
A new class of drugs
The discovery of a protein called Smac gave scientists more ideas of how the action of IAPs could be disrupted. Studying how cells self-destruct, researchers found that when a cell has reached the decision to die, the Smac protein is released to neutralise IAPs and allow apoptosis to happen.
This led to the development of a new class of drugs – Smac mimetics. These drugs, currently in clinical trials for different forms of cancer including breast, mimic the function of Smac leading cancer cells to self-destruct.
Using Smac mimetics to remove the barrier from the road leading towards cell death is a brilliant idea. However, the reality has proven to be a bit more complicated. Although clinical trials suggest that Smac mimetics are safe to use and are well tolerated, these drugs show little activity when administered on their own.
Removing the blockade caused by IAPs is not enough, as other signals driving a cell to self-destruct also need to be present. Researchers now face the challenge of finding ways to enhance the activity of Smac mimetics with the right combinations of treatment.
Switch from survival to death in the hands of RIPK1
Professor Pascal Meier and his team at the Breast Cancer Now Toby Robins Research Centre at the Institute of Cancer Research, London are investigating how healthy cells decide to self-destruct when they need to, and how we can force cancer cells to self-destruct. Their recent work has shed new light on how we can drive cell death which also turns on a person’s own immune system to fight breast cancer.
Professor Meier’s research has focused on a protein called RIPK1, which can direct the cell to a pro-survival or a pro-death path. RIPK1 takes on this task reacting to inflammation signals arising from immune response or treatment with drugs. His team has recently discovered that the decisions made by RIPK1 are influenced by two types of molecular tags: a ubiquitin tag and a phosphate tag, which a handful of other proteins can attach to RIPK1.
The importance of tags
Their newest experiments have shown that a protein called Mind Bomb-2 can prevent RIPK1 from choosing the cell death path. Mind Bomb-2 does this by attaching a ubiquitin tag to RIPK1. This turns off RIPK1’s activity and inhibits its killing potential. Importantly, they have also shown that blocking Mind Bomb-2 can direct cancer cells towards the death route.
But Mind Bomb-2 isn’t the only protein affecting RIPK1’s verdict. Professor Meier has also found that a tag added by the cIAP protein can lead to the destruction of RIPK1 before it even makes the decision. And a protein called MK2 can also protect cells from dying by tagging RIPK1 with a phosphate tag. In a similar way to Mind Bomb-2, blocking these proteins could make cancer cells more vulnerable.
To be or not to be: looking to the future
Like the works of Shakespeare, revealing these complex processes has taken decades of pain-staking work. It’s thanks to world-leading scientists like Professor Meier, whose team has been studying cancer cell death at our Research Centre since 2000, that we’re now seeing the exciting potential of these discoveries to make a difference for patients.
Being able to turn cell death back on in cancer could help reduce the doses of chemotherapy or radiotherapy needed to kill a patient’s cancer cells. And making cancer cells die in a way that turns the immune system against them, could give patients a better chance of surviving the disease.
This has led Professor Meier to start a new drug discovery project working with Professor Spiros Linardopoulos at the Breast Cancer Now Research Centre. Professor Meier believes that in the long term his recent discoveries will lead to new anti-cancer drugs, and we’re excited to see what breakthroughs the future holds.