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Cold viruses point the way to new cancer therapies

Cold Virus

Salk researchers discovered that a small protein produced by cold viruses disables large cellular machines involved in growth, replication and cancer. These proteins accomplish this by forming a three-dimensional web inside a cell's nucleus (yellow) that traps these components. The findings point the way to new approaches to targeting and destroying tumors.

Cold viruses generally get a bad rap, which they've certainly earned, but new findings by a team of Salk scientists suggest that these viruses might also be a valuable ally in the fight against cancer.

Adenovirus, a type of cold virus, has developed molecular tools—proteins—that allow it to hijack a cell's molecular machinery, including large cellular machines involved in growth, replication and cancer suppression. The scientists identified the construction of these molecular weapons and found that they bind together into long chains (polymers) to form a three-dimensional web inside cells that traps and overpowers cellular sentries involved in growth and cancer suppression. The findings, published in Cell, suggest a new avenue for developing cancer therapies by mimicking the strategies employed by the viruses.

"Cancer was once a black box," says Clodagh O'Shea, an assistant professor in Salk's Molecular and Cell Biology Laboratory, who led the study. "The key that opened that box was revealing the interactions between small DNA tumor virus proteins and cellular tumor suppressor complexes. But without knowing the structure of the proteins they use to attack cells, we were at a loss for how these tiny weapons win out over much larger tumor suppressors."

O'Shea's team studied E4-ORF3, a cancercausing protein encoded by adenovirus, which prevents the p53 tumor suppressor protein from binding to its target genes. "Most cellular polymers and filaments form uniform, rigid chains," O'Shea says. "But E4-ORF3 is the virus's Swiss army knife—it assembles into something that is highly versatile. It has the ability to build itself into all sorts of different shapes and sizes that can capture and deactivate the many defenses of a host cell."

In collaboration with scientists from the National Center for Microscopy and Imaging Research at the University of California, San Diego, O'Shea's team used new techniques to reveal the ultrastructure of the remarkable polymer that E4-ORF3 assembles in the nucleus— something that previously had proven difficult since the polymer is effectively invisible using conventional electron microscopy.

The findings may help scientists develop small molecules—the basis for the vast majority of current drugs—capable of destroying tumors by binding and disrupting large and complex cellular components that allow cancer cells to grow and spread. Understanding how viruses overcome healthy cells may also help scientists engineer tumor-busting viruses, which offer a new and potentially self-perpetuating cancer therapy. Such modified viruses would destroy only cancer cells, because they could only replicate in cells in which the p53 tumor suppressor has been deactivated. When a cancer cell is destroyed, it would release additional copies of the engineered viruses, which would seek out and kill remaining cancer cells that have spread throughout the body.