Amplifying cell death signals causes pre-cancerous cells to self-destruct

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Washington, August 17 : Rockefeller University scientists say that they have devised a way to amplify death signals that make a cell multiplying in a dangerously abnormal way to kill itself before becoming cancerous.

The researchers say that the trick is to inactivate a protein that normally helps cells to avoid self-destruction.

Lead researcher Hermann Steller, Strang Professor and head of the Laboratory of Apoptosis and Cancer Biology, claims that this is the first study to reveal the mechanism whereby a class of proteins called IAPs (inhibitor of apoptosis proteins) regulates cell death.

A research article in the journal 'Genes and Development' says that by exposing the mechanism in mice, the finding also marks a breakthrough in the field, and opens the door for developing a new class of drugs that may aid in cancer therapy and prevention.

"In a way, these mice are guiding clinical trials. We now can study how IAPs contribute to the development of cancer in a living animal and develop drugs to prevent or thwart the disease," says Steller, who is also a Howard Hughes Medical Institute investigator.

IAP inhibiting apoptosis (programmed cell death) to keep cells alive by directly binding to executioner enzymes called caspases. However, so far, precisely how IAPs save cells from death has remained unclear.

With graduate student Andrew Schile and postdoc Maria Garcia-Fernandez, Steller studied the X-linked inhibitor of apoptosis protein (XIAP), and the role of its largely ignored RING domain, which has been implicated in promoting cell death as well as survival.

They found that genetically targeting and removing RING affected only some cell types in healthy mice.

Even though the mice without the RING had more cell death than the mice with the RING, according to the researchers, both lived normal lives under normal laboratory conditions.

Comparing mice that were genetically predisposed to developing cancer, the research group found that the animals without the RING lived twice as long as those with it.

"Cancer cells thrive by disabling the molecular machinery that tells sick cells to die. By removing the RING, we wanted to see whether we would trick the machinery to turn back on. And that's what happened. Cells die more readily, making it much more difficult for cancer to be established," says Steller.

He and his colleagues specifically showed that the RING transfers molecular tags on caspases that label these enzymes for destruction.

According to him, the more tags, the stronger the signal to save the cell from death.

However, when the RING was removed, fewer molecular tags were transferred to caspases, and, often, the signal to save the cell from death was not strong enough. Thus, more cells died.

The researchers insist that more research is needed to identify the IAP genes that are important in the development of cancer.

"We need to use genetics to sort out which individual IAPs contribute to tumors and which IAPS we need to target in order to cure cancer. This was a very big step in understanding what role IAPs play in cancer, but it isn't the last," says Steller.


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