Apoptosis is needed in other contexts as well. In a developing embryo apoptosis is needed to remove unnecessary tissue. In addition, failure of apoptosis can lead to autoimmune diseases as well as cancer. (This is why some anti-cancer drugs are also able to treat some autoimmune diseases.)
The following research announcement, which we'll look at in more detail, has a nice capsule summary of apoptosis.
Cells Re-energize To Come Back From The Brink Of Death
Apoptosis is triggered by a variety of factors, including gene mutations that can make the cell become cancerous. During apoptosis, the membrane covering the cell's mitochondria develop holes and leak a molecule called cytochrome c, which triggers the activity of enzymes called caspases. In turn, caspases trigger a series of events that kills the cell.
To amplify a little, here are some of the conditions that can initiate a cell's apoptosis program:
- P53 protein may detect damaged DNA during the G1 phase of the cell division cycle. If it does not prove possible to repair the damaged DNA, P53 can invoke apoptosis.
- The cytokine TNF (tumor necrosis factor) produced by the immune system (specifically, activated macrophages) is an external signal to initiate apoptosis. As the name implies, this is another anti-cancer mechanism.
- Signals produced by cytotoxic T cells of the immune system can also induce apoptosis. This may occur in response to a virus-infected cell. (Much more on T cells: here.)
However, there is a weak spot in the apoposis process: it requires the presence of caspase enzymes. If something has blocked production of essential caspases (which some tumors are able to do), then apoptosis won't work.
Because of this, nature (i. e. evolution) has provided a backup mechanism for programmed cell death, one that does not rely on caspases. The mechanism is called, appropriately, caspase-independent cell death (CICD), and the research announcement mentioned above has this to say about it:
The process by which the membranes develop holes--mitochondrial outer membrane permeability (MOMP)--is often the "point of no return" for self-destruction, said Douglas Green, Ph.D., chair of the St. Jude Immunology department and the study's senior author. MOMP triggers apoptosis, but if apoptosis fails because there is no caspase available, the backup program called caspase-independent cell death (CICD) takes over the process.
Previous research has shown that cells that become cancerous lack caspase and other proteins needed to support apoptosis after MOMP releases cytochrome c. But this victory over death is short-lived if CICD is activated.
Unfortunately, tumors (successful ones anyway) eventually develop the ability to cheat this death program as well:
However, some cancerous cells not only dodge death from apoptosis by eliminating caspase activation, but they also foil CIDC. "Our study sought to understand how a cancer cell without caspase activation bypasses CICD as well," Green said.
The St. Jude team discovered that a cell that lacks caspase activation and cannot undergo apoptosis increases the levels of an enzyme called GAPDH in order to counteract CICD. GAPDH appears to prevent CICD by supporting the functioning of the mitochondria and triggering the activity of certain genes that prevent or repair cell damage. The findings also suggest that the increase in GAPDH provides energy to increase autophagy--the process by which a cell "chews up" debris and broken components, such as damaged mitochondria. After disposing of damaged mitochondria the cell can replace these vital components.
"We found that in the absence of caspase activation, cells that avoided CICD took about a week or so to begin multiplying again," Green said. "This might represent the time it takes for the cell to restore enough mitochondria to allow the cell to function normally."
Cancer cells are (unfortunately) amazing in their resourcefulness. Of course, this results from a kind of evolutionary process, in which cancer cells that are successful at cheating death and reproducing are those which have developed, by chance, the necessary mutations.
The role played by mitochondria and caspases in apoptosis is quite important for an understanding of both cancer and autoimmune diseases. It's worth remembering the connection, since further research will certainly tell us a lot more about these interrelated processes. Here's an example of earlier research on the subject: Proteins are Key to Cell Death in Heart Disease, Stroke and Degenerative Conditions
Tags: apoptosis, caspase, mitochondria, cancer
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