Researchers at MIT have keyed in on a critical molecule, a protein that can hasten the cell death — by using ingenious ways to coax cells into death.
Programmed cell death, or apoptosis, entails a biochemically programmed inner process that shapes the structure and destiny of cells and tissues in a multicellular life form. The cell suicide is mediated by phenomena such as blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation. A number of signal transduction pathways are involved that regulate the life and death of organisms as we see.
For instance, under conditions of excessive DNA damage, cells are usually compelled to commit suicide. However, cancer cells are a different kettle of fish in that they ignore these signals, and continue to proliferate even after chemotherapy drugs have ravaged their DNA.
MIT researchers therefore sought an ingenious way to outmanoeuvre the death-defying pathways of certain cells.
Leona Samson, Ph.D, and colleagues at MIT's Center for Environmental Health Sciences and Koch Institute for Integrative Cancer Research, identified a key protein involved in an alternative death pathway known as programmed necrosis. By driving the cancer cells resistant to apoptosis toward necrosis instead, the researchers have engineered the path to cell destruction. They have also opened the doors to novel drug development. The strategy could help the industry design molecules that mimic the effects of this protein that can destroy cancer cells that are resistant to apoptosis.
In contrast to apoptosis, which is orderly and sequential in disposing of a dying cell, necrosis results in the premature death of cells in living tissue, using external means such as infection, toxins, or trauma that result in the unregulated digestion of cell components.
"People really used to think of necrosis as cells just falling apart, that it wasn't programmed and didn't require gene products to make it happen," says Dr. Samson, in the MIT news release. "In the last few years it has become increasingly clear that this is an active process that requires proteins to take place."
Reporting in the May 10 online edition of the journal Genes and Development, professor Samson and colleagues explain that a protein called ALKBH7 plays a key role in controlling the programmed necrosis pathway. Occurring as nine different proteins, the ALKBH has been implicated in DNA repair, similar to the original E. coli version. They play a critical role in repairing DNA damage caused by alkylating agents found in pollutants such as fuel exhaust and tobacco smoke as well as cancer drugs. The researchers show that the ALKBH7 protein promotes cell death. They found that when the ALKBH7 levels were lowered in human cells grown in the lab, the cells survived DNA damage compared to cells with normal ALKBH7 levels. The investigators found that programmed necrosis sets in when healthy cells suffer massive DNA damage from alkylating agents.
The researchers show that necrosis is initiated by an enzyme called PARP. It becomes increasingly active following DNA damage. It acts by shutting down the cellular energy production mediated by the molecules ATP and NAD. The MIT researchers discovered that ALKBH7 prevents ATP and NAD levels from returning to normal by disrupting the function of mitochondria, the cellular components involved in energy production. As the energy supply is cut off, the cell has no way of surviving, and dies, basically of starvation.
"Our results uncover a novel role for a mammalian AlkB homolog in programmed necrosis, presenting a new target for therapeutic intervention in cancer cells that are resistant to apoptotic cell death," the researchers conclude.
