Study IDs key protein for cell death, offers way to kill cancer cells by forcing them into programmed-death pathway

May 14, 2013 by Anne Trafton, Massachusetts Institute of Technology
To determine the location of ALKBH7 in cells, MIT researchers engineered these cells to express ALKBH7 bound to green fluorescent protein (GFP). The cells’ mitochondria express a red fluorescent protein. In cells where ALKBH7 is present in the mitochondria, the green and red signals mix and appear yellow. Credit: JENNIFER JORDAN AND DRAGONY FU

When cells suffer too much DNA damage, they are usually forced to undergo programmed cell death, or apoptosis. However, cancer cells often ignore these signals, flourishing even after chemotherapy drugs have ravaged their DNA.

A new finding from MIT researchers may offer a way to overcome that resistance: The team has identified a key protein involved in an alternative death pathway known as programmed . Drugs that mimic the effects of this protein could push that are resistant to apoptosis into necrosis instead.

While apoptosis is a tightly controlled procedure that breaks down and disposes of the dying cell in a very orderly way, necrosis is a messier process in which the cell's membrane ruptures and its contents spill out.

"People really used to think of necrosis as cells just falling apart, that it wasn't programmed and didn't require to make it happen," says Leona Samson, a member of MIT's Center for and Koch Institute for Integrative . "In the last few years it has become more clear that this is an active process that requires proteins to take place."

In the May 10 online edition of the journal Genes and Development, Samson and colleagues report that a protein known as ALKBH7 plays a key role in controlling the programmed necrosis pathway. Dragony Fu, a former postdoc in Samson's lab, is the paper's lead author, and postdoc Jennifer Jordan is also an author.

Unexpected findings

ALKBH7 belongs to a family of proteins first discovered in E. coli about a dozen years ago as part of a DNA-repair mechanism. In humans, there are nine different ALKBH proteins, which Samson's lab has been studying for several years.

Most of the mammalian ALKBH proteins appear to be involved in , similar to the original E. coli version. In particular, they respond to DNA damage caused by . These agents can be found in pollutants such as fuel exhaust and , and are also used to treat cancer.

In the new paper, Samson, a professor of biology and biological engineering, and her colleagues found that ALKBH7 has an unexpected effect. When the researchers lowered ALKBH7 levels in human cells grown in the lab, those cells were much more likely to survive DNA damage than cells with normal ALKBH7 levels. This suggests that ALKBH7 actually promotes .

"That was a surprising finding, because previously all of these ALKBH proteins were shown to be helping the cell survive when exposed to damage," says Fu, who is now a visiting research fellow at the University of Zurich.

Upon further investigation, the researchers found that when healthy cells suffer massive DNA damage from alkylating agents, they enter the programmed necrosis pathway. Necrosis, which can also be initiated by bacterial or viral infection, is believed to help the body's immune system detect threats.

"When dying cells release their contents during necrosis, it serves as a warning signal for your body that there is a virus there and recruits macrophages and other immune cells to the area," Fu says.

Potential drug targets

The findings suggest that when DNA is so badly harmed that cells can't repair it, the programmed necrosis pathway kicks in to prevent cells with major genetic damage from potentially become cancerous.

Other researchers have shown that some types of cancer cells have much lower ALKBH7 levels than normal cells. This suggests that the cancer cells have gained the ability to evade programmed necrosis, helping them to survive, Fu says.

The necrosis pathway appears to be initiated by an enzyme called PARP, which becomes hyperactive following DNA damage and shuts down the cell's production of two molecules that carry energy, ATP and NAD. The MIT team found that ALKBH7 prevents ATP and NAD levels from returning to normal by disrupting the function of mitochondria—the cell structures that generate energy for a cell.

Without an adequate supply of those critical energy-carrying molecules, the cell cannot survive and undergoes necrosis. In cells that lack ALKBH7, ATP and NAD levels rebound, and the cells survive, carrying a heavy burden of .

The researchers are now investigating the molecular details of the programmed necrosis pathway in hopes of identifying ways to activate it in cancer .

"The observations reported in this paper open up the possibility that novel treatments could be developed to treat tumors that are relatively resistant to killing via the apoptotic pathway," says Ashok Bhagwat, a professor of chemistry at Wayne State University who was not part of the research team.

The paper is titled "Human ALKBH7 is required for alkylation and oxidation-induced programmed necrosis."

Explore further: Measuring enzyme levels in cancer patients may reveal healthy cells' ability to survive chemotherapy

More information: genesdev.cshlp.org/content/ear … 33.113.full.pdf+html

Related Stories

Measuring enzyme levels in cancer patients may reveal healthy cells' ability to survive chemotherapy

April 5, 2013
New research from MIT may allow scientists to develop a test that can predict the severity of side effects of some common chemotherapy agents in individual patients, allowing doctors to tailor treatments to minimize the damage.

Same signaling enzymes can trigger two different processes in the cell

March 18, 2013
Stroke, heart attacks and numerous other common disorders result in a massive destruction of cells and tissues called necrosis. It's a violent event: As each cell dies, its membrane ruptures, releasing substances that trigger ...

A protein's role in helping cells repair DNA damage

November 1, 2012
(Medical Xpress)—In a new study, University at Buffalo scientists describe the role that a protein called TFIIB plays in helping cells repair DNA damage, a critical function for preventing the growth of tumors.

DNA-repairing protein may be key to preventing recurrence of some cancers

January 28, 2013
Just as the body can become resistant to antibiotics, certain methods of killing cancer tumors can end up creating resistant tumor cells. But a University of Central Florida professor has found a protein present in several ...

Unexpected discovery highlights new role for cell death regulator

June 14, 2012
An unexpected discovery of how the body controls cell death has revealed a potential new therapeutic target.

Cancer cell metabolism kills

April 15, 2013
Adenosine-5'-triphosphate (ATP) is the main energy source for all forms of work inside our cells. Scientists from the University of Helsinki, Finland, have found that even a short-term shortage of ATP supply can be fatal ...

Recommended for you

Epigenetics study helps focus search for autism risk factors

January 16, 2018
Scientists have long tried to pin down the causes of autism spectrum disorder. Recent studies have expanded the search for genetic links from identifying genes toward epigenetics, the study of factors that control gene expression ...

Group recreates DNA of man who died in 1827 despite having no body to work with

January 16, 2018
An international team of researchers led by a group with deCODE Genetics, a biopharmaceutical company in Iceland, has partly recreated the DNA of a man who died in 1827, despite having no body to take tissue samples from. ...

Study advances gene therapy for glaucoma

January 16, 2018
While testing genes to treat glaucoma by reducing pressure inside the eye, University of Wisconsin-Madison scientists stumbled onto a problem: They had trouble getting efficient gene delivery to the cells that act like drains ...

The surprising role of gene architecture in cell fate decisions

January 16, 2018
Scientists read the code of life—the genome—as a sequence of letters, but now researchers have also started exploring its three-dimensional organisation. In a paper published in Nature Genetics, an interdisciplinary research ...

How incurable mitochondrial diseases strike previously unaffected families

January 15, 2018
Researchers have shown for the first time how children can inherit a severe - potentially fatal - mitochondrial disease from a healthy mother. The study, led by researchers from the MRC Mitochondrial Biology Unit at the University ...

Genes that aid spinal cord healing in lamprey also present in humans

January 15, 2018
Many of the genes involved in natural repair of the injured spinal cord of the lamprey are also active in the repair of the peripheral nervous system in mammals, according to a study by a collaborative group of scientists ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.