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Self-destructing Precancerous Cells

Rockefeller University scientists have found a way using mice to amplify the signals that trigger cells to die when they begin to multiply.

Rockefeller University scientists, who reported on their research in the August 15 issue of Genes and Development, have found a way using mice to amplify the signals that trigger cells to die when they begin to multiply in dangerously abnormal ways, before turning cancerous.

How’d they do it? They exposed, for the first time in a living animal, the mechanism by which inhibitors of apoptosis protein (IAPs) inhibit programmed cell death (by directly binding to the executioner enzyme caspase), setting the stage for development of a new drug class for cancer therapy and prevention. The team looked at the X-linked IAP (XIAP), particularly its RING domain—implicated in cell death and cell survival promotion—and determined that, in mice that were genetically predisposed to develop cancer, those who had the RING genetically targeted and removed by the researchers lived twice as long as those with it. “Cancer cells thrive by disabling the molecular machinery that tells sick cells to die,” said lead researcher Hermann Steller, Strang Professor and head of the Laboratory of Apoptosis and Cancer Biology. “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.”

But Steller’s work isn’t finished, as a number of IAP genes are known to exist. “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,” said Steller. “This was a very big step in understanding what role IAPs play in cancer, but it isn’t the last.”

More on IAPS

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Tumors Acquire Inhibitor of Apoptosis Protein (IAP)-mediated Apoptosis Resistance through Altered Specificity of Cytosolic Proteolysis

Melanoma inhibitor of apoptosis protein (ML-IAP) is a target for immune-mediated tumor destruction