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Smac-ing back at cancer cells

By mimicking a molecular switch that triggers cell death, researchers have killed cells grown in the laboratory from one of the most resilient and aggressive cancers a virulent brain cancer known as glioblastoma. The new approach to tricking the cell-death machinery could be applied to a wide range of cancers where this pathway, known as apoptosis, has been inactivated.

The researchers -- led by Xiaodong Wang, a Howard Hughes Medical Institute investigator at the University of Texas Southwestern Medical Center at Dallas and his colleagues Patrick Harran and Jef De Brabander -- published their findings in the September 3, 2004, issue of the journal Science.

Many cancer cells are particularly hardy because they have switched off the apoptotic machinery at one point or another, protecting them from the suicide process that their aberrant behavior would otherwise trigger.

To reactivate the cell-death pathway in cancer cells, the researchers sought to create a molecular mimic of a protein called Smac, which promotes apoptosis. Normally, when apoptosis is activated in cells that are damaged or no longer needed, Smac is released from the mitochondria, which are the cell's power plants. Once released, Smac binds to a group of gatekeeper proteins known as "inhibitor of apoptosis proteins" (IAPs), which normally hold in check the cell's chief executioner enzymes. These enzymes, called caspases, wreak lethal havoc in cells targeted for apoptosis. Smac's action is why it was named the "second mitochondria-derived activator of caspases."

Specifically, Wang and his colleagues sought to make a small molecule to mimic the function of the Smac protein, since a smaller molecule is better able to pass through the cell membrane to reach the cell's interior, where IAP-caspase resides.

"The idea for making this inhibitor molecule first arose in previous studies when our collaborator Dr. Yigong Shi solved the crystal structure of Smac interacting with
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Contact: Jennifer Michalowski
michalow@hhmi.org
301-215-8576
Howard Hughes Medical Institute
8-Sep-2004


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