Cell death

Cells can die because they are damaged, but most cells die by killing themselves.

There are several distinct ways in which a cell can die. Some occur by an organised, ‘programmed’ process. Some cell death processes leave no trace of the dead cell, whereas others activate the immune system with substances from the dead cell.

Apoptosis: is a form of cell death that prevents immune activation. Apoptotic cells have a particular microscopic appearance. The cell activates proteins called caspases that are normally dormant. These caspases dismantle the cell from within. The apoptotic cell breaks into small packages that can be engulfed by other cells. This prevents the cell contents leaking out of the dying cell and allows the components to be recycled.

Necrosis: occurs when a cell dies due to lack of a blood supply, or due to a toxin. The cells’ contents can leak out and damage neighbouring cells, and may also trigger inflammation.

Necroptosis: is similar in appearance to necrosis, in that the dying cell’s contents can leak out. However, like apoptosis, necroptosis is a programmed suicide process triggered by specific proteins in the dying cell.

Pyroptosis: is a form of cell death that occurs in some cells infected with certain viruses or bacteria. A cell dying by pyroptosis releases molecules, called cytokines, that alert neighbouring cells to the infection. This triggers inflammation, a protective response that restricts the spread of the viruses and bacteria.

Many proteins have been discovered that control whether a cell dies by the processes of apoptosis, necroptosis or pyroptosis.

Some key cell death control proteins include:

• Caspases: these enzymes are switched on in apoptotic cells, and digest other proteins to bring about cell death. Some caspases have roles in processes other than cell death.
• Bcl-2 family proteins: these proteins interact with each other to determine whether a cell undergoes apoptosis or stays alive. Some Bcl-2 family proteins promote survival, and block apoptosis. Others are ‘pro-death’, and trigger apoptosis.
• Death receptors: these are proteins on the surface of the cell. When they are bound by certain cytokines (hormone-like signalling proteins), they cause changes in the cell that can lead to cell death.
• RIP kinases: two proteins called ‘RIP1 kinase’ and ‘RIP3 kinase’ trigger necroptosis.
• IAPs: or ‘inhibitor of apoptosis proteins’ can prevent cell death. They can do this by blocking several cell death proteins including caspases and RIP1 kinase.
• SMAC/Diablo: is an inhibitor of IAPs. In healthy cells, SMAC is stored away from IAPs, in parts of the cell called mitochondria. When cell death is triggered, SMAC can leak out and block IAPs function. Thus, the release of SMAC out of mitochondria can promote cell death.

Many diseases are associated with abnormal cell death. Some examples of this are:

• cancer: cancer cells often resist cell death, even after anti-cancer treatment.
• autoimmunity e.g. Lupus, type 1 diabetes: immune cells that attack the body’s own tissues normally die. If this cell death does not occur it can cause diseases such as lupus or type 1 diabetes.
• viral infection: viruses need to keep a cell alive in order to reproduce. Cell death can therefore prevent viral replication.
• heart attack: many cells, including those in the heart and brain, trigger their apoptosis machinery when they lose their blood supply.

Understanding how proteins such as the Bcl-2 family control cell death has led to the development of new drugs to block their function. These have the potential to cause the death of cancer cells, or the immune cells that cause autoimmune disease.

One set of drugs, called ‘BH3 mimetics’ trigger apoptotic cell death. They do so by preventing the action of ‘pro-survival’ Bcl-2 family proteins. Unless blocked, these pro-survival proteins help cancer cells stay alive, even after anti-cancer treatments such as chemotherapy.

Clinical trials are underway to determine whether BH3 mimetics can be used to treat certain cancers. BH3-mimetics might also potentially help treat autoimmune diseases by killing disease-causing white blood cells.

SMAC-mimetics are agents that, like the SMAC protein, enhance cell death. They do this by stopping IAPs from blocking cell death. They might also be able to help cells die so that chronic viral infections can be cleared.

There is also considerable interest in agents that can prevent cell death. These could have applications for treating conditions in which there is unwanted cell death, such as stroke, heart attack or neurodegenerative disorders.