Cell Death: New Apoptosis Pathway Discovered

Alternate cell-death program identified
Researchers find chemical inhibitor of nonapoptotic programmed cell-death process called ‘necroptosis’

Although research over the past decade has shown that apoptosis is likely not the only type of programmed cell death, little is known about what other mechanisms may look like. In this week’s online Nature Chemical Biology, Junying Yuan at Harvard University and her colleagues reveal such a pathway by identifying a chemical that blocks nonapoptotic programmed cell death, both in vitro and in a mouse model of ischemic brain injury.

The paper shows that the chemical, Nec-1, has no effect on apoptosis—only on this programmed necrosis-like death, which Yuan and her colleagues term “necroptosis.” The researchers also show that although necroptosis shows some characteristics of autophagy, this is a downstream consequence of necroptotic signaling, not an upstream effector of it.

“There have been many hints that there are ways to kill cells” other than the classical apoptotic pathway, Shai Shaham, of the Rockefeller University, told The Scientist. “The one thing that has been lacking so far has been a way to figure out what proteins are involved in these other pathways…”

What’s been missing, according to Yuan, is proof that a common pathway carries out nonapoptotic programmed cell death in the multiple types of cells in which it’s been observed. “So we asked the question: Can we find a chemical that inhibits all of those cell deaths?” Yuan told The Scientist.

Yuan and her colleagues screened a chemical library of about 15,000 compounds, looking for inhibitors of an alternate death pathway. When human cells were treated with tumor necrosis factor-?, a ligand for the Fas/TNFR family, along with a pan-caspase inhibitor, many cells died a necrosis-like death, as expected. They found one small molecule, however, that prevented these cells from dying.

The researchers tested this chemical, which they name necrostatin-1, or Nec-1, in many different types of cells and found that it inhibited TNF?-induced necrosis in all of them. This is the first direct evidence of a common, alternative form of programmed cell death, Yuan said.

The frequency of necrostatin-1 appears to be 44466.7 and this frequency should be used with caution.

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