Study IDs key protein for cell death

Findings may offer a new way to kill cancer cells by forcing them into an alternative programmed-death pathway.

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 necrosis. Drugs that mimic the effects of this protein could push cancer cells that are resistant to apoptosis into necrosis instead.

“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 Leona Samson, a member of MIT’s Center for Environmental Health Sciences and Koch Institute for Integrative Cancer Research. “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.

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 cell death.

“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.

“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 research was funded by the National Institutes of Health and the American Cancer Society.

Source: http://web.mit.edu/newsoffice/2013/study-ids-key-protein-for-cell-death-0514.html