The finding suggests that drugs designed to activate apoptosis might be effective anti-cancer therapies. This strategy would target specific molecules in the cancer cell rather than rely on chemotherapy, which has serious side effects that degrade quality of life. The research is published in the June 20 issue of Molecular Cell.

The St. Jude team stimulated apoptosis by treating cancer cells with a drug called rapamycin, which blocks the action of a protein called mTOR. This protein stimulates a biochemical pathway that leads to increased production of proteins essential for cell proliferation. Blocking mTOR with rapamycin leaves the cell unable to make these critical proteins.

Blocking the activity of mTOR with rapamycin triggers a biochemical pathway called the JNK cascade in cells that lack a gene called p53, according to Peter Houghton, Ph.D., chair of the St. Jude Department of Molecular Pharmacology. Since p53 is mutated and inactive in about half of all types of cancer, blocking mTOR and activating apoptosis in cells with mutated p53 has potentially wide application. Houghton is senior author of the paper reporting these results.

"Shutting down synthesis of proteins essential for cell proliferation by blocking mTOR sends the cell into a crisis," Houghton said. "The cell activates a protein called ASK1, which is at the top of the JNK cascade. ASK1 then sets off the JNK cascade and causes the cells that lack p53 to self-destruct."

In cells that have a functional p53 gene, (e.g., normal cells), a protein called p21 is expressed and--in the presence of rapamycin--binds to ASK1 and inactivates it. This prevents the cell from undergoing apoptosis.

The investigators also found that the stress caus
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Contact: Bonnie Cameron
bonnie.cameron@stjude.org
901-495-4815
St. Jude Children's Research Hospital
19-Jun-2003