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Biological Chemistry

Triggering The Kiss Of Death

Small molecule spurs protein executioner into action

by Sarah Everts
September 13, 2006 | APPEARED IN VOLUME 84, ISSUE 38

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Credit: COURTESY OF PAUL HERGENROTHER
Apoptosis can be initiated through one of two cell-signalingpathways. Both pathways converge on caspase-3, a protein that acts asthe cell's executioner. PAC-1 bypasses both pathways and initiatesapoptosis by inducing procaspase-3 to cleave itself to yield activecaspase-3.
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Credit: COURTESY OF PAUL HERGENROTHER
Apoptosis can be initiated through one of two cell-signalingpathways. Both pathways converge on caspase-3, a protein that acts asthe cell's executioner. PAC-1 bypasses both pathways and initiatesapoptosis by inducing procaspase-3 to cleave itself to yield activecaspase-3.

Activating an executioner sounds like an unwise proposition, but the idea has produced a potent new small molecule for killing cancer cells, according to work presented at the ACS national meeting in San Francisco.

Many proteins are involved in triggering a cell's demise, but the protein caspase-3 does the dirty work. This executioner protein catalyzes the hydrolysis of more than 100 protein targets. These cleavage events ultimately lead to cell suicide, or apoptosis.

Most tumors have disruptions in the protein signal cascades that produce active caspase-3. These disruptions thwart cell suicide and allow the cancer to grow unchecked. As such, many cancer researchers are trying to reactivate the signals along this suicide pathway. Now, a group of chemists have cut to the chase. They discovered PAC-1, the first small molecule that can trigger cell death directly by activating caspase-3.

"With PAC-1 we bypass the damaged apoptotic cascade, which is a hallmark of cancer, and induce cell death," said Paul J. Hergenrother from the University of Illinois, Urbana-Champaign.

Karson S. Putt, a graduate student in Hergenrother's group, presented the PAC-1 discovery during the Division of Medicinal Chemistry's award ceremony at the meeting. It's also the subject of a recent paper in Nature Chemical Biology (DOI: 10.1038/nchembio814).

PAC-1 likely acts by interfering with one of caspase-3's safety features. The protein is normally in an inactive form called procaspase-3 until a domain of the protein is chopped off, thereby creating active caspase-3. A further three-amino-acid safety catch prevents procaspase-3 from activating itself by cleaving itself. PAC-1 is believed to work by interfering with this safety catch, thereby allowing procaspase-3 to activate itself and initiate cell death.

Unlike inhibitors that work stoichiometrically, PAC-1 is a catalytic activator, Hergenrother said. "This is a benefit. One molecule of PAC-1 will activate procaspase-3 to produce caspase-3. Then PAC-1 is free to activate another one."

"This is a novel strategy for a cancer therapy," commented Michael F. Olson of the Beatson Institute for Cancer Research in Glasgow, Scotland. "Going straight to one of the key proteins that actually kills the cell and directly activating it could induce the death of cancer cells that are insensitive to many forms of standard chemotherapy."

Initial research with patient tissue samples and mouse models shows that PAC-1's ability to destroy cancer cells is related to the levels of procaspase-3 in a cell, Hergenrother said. "Since tumor procaspase-3 levels can be measured, one might be able to predict a priori what types of patients would respond to a procaspase-3 activator. This is a step toward personalized cancer therapy."

Next up, Hergenrother hopes to crystallize PAC-1 with the caspase-3 protein. Toxicological tests are also ongoing.

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