Paradox protein starts and stops cancer, study finds

Laura Attardi

A protein previously implicated in colon cancer now appears to have an additional role in preventing cells from dividing, a finding that could lead to new cancer therapies.

The unusual protein, called Prl-3, appears to both prevent and provoke cancer. It was known to be active in colon cancer cells, playing a role in allowing the cells to become more invasive. The new findings by researchers at the School of Medicine suggest that the protein is also part of a complex pathway that prevents a cell from dividing after receiving cancer-causing DNA damage.

"This paradox was extremely curious," said Laura Attardi, PhD, associate professor of radiation oncology. "We thought it would be interesting to understand what that was all about." Attardi is the senior author on the paper, which appeared in the May 8 issue of Molecular Cell.

It turns out that a cell needs exactly the right level of Prl-3 in order to maintain the normal state. "There's a critical level of protein that's needed and mucking around with that isn't tolerated," said Attardi, who is also a member of the Stanford Cancer Center.

Attardi's particular interest has been in a protein called p53, which acts as a cellular brake, preventing a cell from dividing if it has incurred possible cancer-causing mutations. When activated, this brake switches on hundreds of genes that then churn out proteins, all of which work together to prevent the cell from dividing. This mechanism gives the cell time to repair the DNA damage before it can lead to cancer.

The protein is so effective at shutting down cancer before it starts that most cancerous cells have mutated versions of the p53 gene. Once a cell has a mutation in p53 and can no longer switch on the cellular braking mechanism, it can continue its out-of-control divisions that are a hallmark of cancer.

Curious about which genes are switched on by p53 as part of the cellular brake, Attardi and postdoctoral scholar Shashwati Basak, PhD, studied normal cells that had been exposed to a drug that causes DNA damage—the type of genetic damage that causes p53 to initiate the braking process. She then examined which genes were activated by the p53 brake.

Much of what Attardi and her group found was expected, given that p53 has been the subject of extensive research over the past few decades. However, the fact that the prl-3 gene got turned on by p53 caught the their eye. Why was a protein known to provoke cancer also involved in a chain of events that prevents cancer? That conundrum stood out as worthy of further examination.

What that examination turned up is a complicated role for the Prl-3 protein. Attardi said it appears that the quantity of Prl-3 in the cell may define whether it promotes or prevents cancer, in addition to what other proteins are also activated.

Attardi said Prl-3 could be a target for cancer therapies once they better understand what it is doing in the cell. "There could be a small molecule that you could screen for that inhibits prl-3," she said.

Other Stanford researchers include postdoctoral scholars Suzanne Jacobs, PhD, and Adam Krieg, PhD; research assistant Navneeta Pathak; and Amato Giaccia, PhD, the Jack, Lulu and Sam Willson Professor and professor of radiation oncology.

This work was supported by a Stanford Dean's postdoctoral fellowship; a Susan G. Komen postdoctoral fellowship; the Giannini Family Foundation; the Damon Runyon Cancer Research Foundation; and the Donald E. and Delia B. Baxter Foundation.