Cancer "Survival" Structure Deciphered By Salk Scientists
LA JOLLA, CALIF. -- It's a molecule that endows cancer cells with their pernicious ability to persevere.
Now, scientists at The Salk Institute have deciphered the three-dimensional structure of this molecule, appropriately named "survivin." Their work suggests how drugs might block its activity and lead cells to commit "suicide."
"There's been a lot of interest in survivin as a drug target, because it is present at high levels in a number of cancer cells which gives them a way of surviving and multiplying," said Joseph P. Noel, a Salk associate professor and senior author of the study. "Knocking out its activity is exactly what we'd like to make cancer cells do. The three-dimensional shape may allow scientists to design molecules in the laboratory that can stick to survivin and knock out its activity."
He added that survivin is turned on in almost half the malignancies seen in the clinic -- particularly breast, lung, prostate and colon cancers, all among the most commonly occurring cancers.
Survivin's structure, determined by X-ray crystallography and reported in the current issue of Nature Structural Biology, suggests a likely target for drugs to block the molecule's cancer-promoting action.
"We were able to draw a very precise map of this protein and pinpoint the critical regions on its surface that are hot spots for allowing survivin to promote cell division," said Mark A. Verdecia, first author on the study and a graduate student in Noel's laboratory. "This will enable the design of specific inhibitors that can slide into these pockets and prevent survivin from using these critical pockets."
"Turning survivin off triggers a suicide program called apoptosis," said Tony Hunter, co-author and Salk professor. Apoptosis, which translates from Greek as "falling leaves," is a distinct program by which a cell shuts down its activities in an ordered manner and quietly implodes. While this sounds terrible for living organisms, it is actually a very necessary part of life, which allows organisms as a whole to survive and prosper. Cancer cells lose this ability to die; instead they grow and divide indefinitely causing severe and often fatal consequences.
"Triggering apoptosis would therefore be an ideal way of eliminating cancer cells," Hunter added.
Survivin is normally active only in growing embryos or rapidly dividing cells such as those that comprise the immune system.
"We don't know how survivin gets switched on when it shouldn't -- in mature breast or prostate cells, for example," said Noel. "But having the structure in hand gives us a template for the rational design of drugs that can turn it back off."
Survivin is thought to attach to the "mitotic spindle," a foundation in the nucleus of cells that pulls newly divided chromosomes into the two daughter cells created during cell division.
"Its three-dimensional structure suggests that it accomplishes this task by setting the stage for the assembly of this foundation," said Noel. "Tear down this foundation and the cell is unable to pull itself apart and dies. Most important from a clinical perspective, our results indicate how survivin's action might be best blocked."
Co-authors include Han-kuei Huang, Erica Dutl, and Donald A. Kaiser. The study, titled "Structure of the human anti-apoptosis protein survivin reveals a dimeric arrangement," was supported by the National Institutes of Health and the Department of Energy. Hunter is a Frank and Else Schilling American Cancer Society Professor. Huang is supported by the Damon Runyon-Walter Winchell Foundation.
The Salk Institute for Biological Studies, located in La Jolla, Calif., is an independent nonprofit institution dedicated to fundamental discoveries in the life sciences, the improvement of human health and conditions, and the training of future generations of researchers. The Institute was founded in 1960 by Jonas Salk, M.D., with a gift of land from the City of San Diego and the financial support of the March of Dimes Birth Defects Foundation.
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