How to make cancer cells die?
A key cell death protein has been identified
NanoNewsNet based on MIT materials: Study IDs key protein for cell deathWith severe DNA damage, cells usually die as a result of activation of the molecular pathway of programmed cell death – apoptosis.
However, cancer cells often ignore these signals and continue to grow and proliferate even after their DNA is damaged by chemotherapeutic drugs.
A new discovery by scientists at the Massachusetts Institute of Technology (MIT) suggests the possibility of breaking the resistance of cancer cells: researchers have identified a key protein of an alternative pathway of programmed cell death – necrosis. Drugs that mimic the effect of this protein can activate the pathway of programmed necrosis in cancer cells resistant to apoptosis.
While apoptosis is a tightly controlled process that destroys the cell and subsequently removes it from the body in an extremely orderly manner, necrosis is much less organized. In general, its essence boils down to the rupture of the cell membrane and the release of the contents of the cell into the environment.
"Necrosis is commonly thought of as a simple, non–programmed cell decay, a process that does not require gene products," says Leona Samson, PhD, researcher at the Center for Environmental Health Sciences and the Institute for Integrative Cancer Research. David H. Koch Institute for Integrative Cancer Research, MIT. "However, over the past few years it has become clear that this is an active process that requires the presence of certain proteins."
In an article published online in the journal Genes and Development (Human ALKBH7 is required for alkylation and oxidation-induced programmed necrosis), Dr. Samson and her colleagues report that a protein known as ALKBH7 plays a key role in controlling the process of programmed necrosis.
The ALKBH7 protein belongs to a family of proteins discovered about ten years ago in E.coli escherichia coli as part of the DNA repair mechanism. There are nine different ALKBH proteins in the human body, which Professor Samson's laboratory has been studying for several years.
Most mammalian ALKBH proteins, as well as those of E. coli, appear to be involved in DNA repair. In particular, they react to DNA damage by alkylating substances. These substances are present in pollutants such as fuel exhaust and tobacco smoke, but they are also used in the treatment of cancer.
Dr. Samson, a professor of biology and biological engineering, and her colleagues found that the ALKBH7 protein has an unexpected effect: laboratory-grown human cells with reduced levels of ALKBH7 had a much better chance of surviving DNA damage than cells with normal levels of this protein. This certainly proves that ALKBH7 does contribute to cell death.
In the course of further research, the scientists found that with massive DNA damage by alkylating agents in healthy cells, the pathway of programmed necrosis is activated. Necrosis, which can also be initiated by bacterial or viral infection, is believed to help the body's immune system detect threats. The release of their contents from dying cells during necrosis is a warning signal for the body about the presence of a virus and the need to attract macrophages and other immune cells to this area.
The newly obtained data indicate that the pathway of programmed necrosis, which prevents the transformation of cells with significant genetic damage into malignant, is activated when DNA is damaged so seriously that cells can no longer repair it.
Other studies have shown that in some types of cancer cells, ALKBH7 levels are significantly lower than in normal ones. Obviously, cancer cells have developed the ability to avoid programmed necrosis, which helps them survive.
To determine the location of ALKBH7 in cells, MIT scientists linked ALKBH7 to a green fluorescent protein. The mitochondria of the cells express a red fluorescent protein. In cells in which ALKBH7 is present in mitochondria, green and red signals merge into yellow.
Photo: Jennifer Jordan and Dragony Fu.The pathway of programmed necrosis is apparently initiated by the enzyme PARP, which is hyperactivated following DNA damage and turns off the synthesis of two energy-carrying molecules by the cell – ATP and NAD (nicotinamide adenine dinucleotide).
Samson and her group found that ALKBH7 prevents the return of ATP and NAD levels to normal by disrupting the functions of cellular energy generators – mitochondria.
Without enough of these vital molecules, the cell cannot survive and undergoes necrosis. In cells lacking ALKBH7, ATP and NAD levels are restored and the cells survive bearing the heavy burden of DNA damage.
Now Professor Samson and her group are studying the molecular details of programmed necrosis in the hope of finding ways to activate it in cancer cells.
Portal "Eternal youth" http://vechnayamolodost.ru17.05.2013