RING Removal Prompts Death of Cancer Cells

Cancer researchers have found a way to "trick” damaged cells into self-destruction despite the overactivity of a molecular pathway that could put them on the road to unrestricted cancerous growth.

Investigators from Rockefeller University (New York, NY, USA) worked with a line of mice that had been genetically engineered to lack the gene for XIAP (X-linked inhibitor of apoptosis protein), a member of a family of proteins that can bind to and inhibit caspases, the key executioners of apoptosis. Since these proteins are frequently overexpressed in human tumors, they have become major pharmacologic targets for developing new cancer therapeutics.

In a study published in the August 15, 2008, issue of the journal Genes & Development, investigators focused on the XIAP's RING [Really Interesting New Gene] domain. They reported that removal of RING from a line of mice predisposed to cancer inhibited tumor development and doubled the animals' survival time. The RING moiety placed molecular tags on caspases that labeled these enzymes for destruction. With more intensive caspase labeling, the signal to save the cell from death was more effective. However, when RING was removed, fewer molecular tags were transferred to caspases, and the signal to save the cell from death was not sufficient to prevent the cells from dying.

"Cancer cells thrive by disabling the molecular machinery that tells sick cells to die,” said senior author Dr. Hermann Steller, professor of cancer biology at Rockefeller University. "By removing the RING, we wanted to see whether we would trick the machinery to turn back on. And that is what happened. Cells die more readily, making it much more difficult for cancer to be established. 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.”

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