Fish research aids Utah cancer study

Research on zebra fish has helped Huntsman Cancer Institute scientists identify a target that might one day lead to prevention or treatment of colon cancer — the No. 2 cause of cancer deaths in the United States.

The findings, published in the current online Journal of Biological Chemistry, indicate that a process the researchers used to rescue zebra fish from abnormal intestinal development may also head off a series of events known to be involved in development of colon cancer in people.

The scientists "knocked out" the molecule C-Terminal Binding Protein (CTBP) to save the zebra fish from a mutation in the adenomatous polyposis coli (APC) gene. Mutations in the same gene in humans lead to colon polyps, which are the precursor to colon cancer. The APC mutations are involved in 85 percent of human colon cancers, according to David A. Jones, a University of Utah associate professor of oncological sciences and leader of the study.

When the researchers knocked out CTBP production, the zebra fish that had the gene mutation developed normal intestines anyway. Knocking out production in humans, they theorize, might disrupt development of colon cancer.

"We have shown that the protein called CTBP is high in people who have these gene mutations. And it suppresses the enzymes that utilize vitamin A," Jones said. "If you can't use it, the cells don't develop correctly. There's already data in humans that says this is the problem (in colon cancer).

"What the fish allows us to do is test for drugs that do the same thing as knocking out CTBP," Jones said. "We are in the process of testing thousands of undescribed compounds looking for a drug that would do the same thing in humans."

If they find a compound that has that desired effect, it could be studied and might even survive the clinical trial process to become a treatment or prevention for colon cancer one day, he said.

The APC gene controls how much CTBP is present in normal cells of both humans and zebra fish by marking it for destruction. In tumor cells with the genetic mutation, the protein instead accumulates. And since one of the protein's roles is turning off the conversion of vitamin A into retinoic acid in the cell, vitamin A doesn't get used as retinoic acid, which is needed for cell differentiation.

The researchers found that in tissue — whether in fish or humans — with the APC mutations, there's a relationship between the high CTBP levels and inability to manufacture adequate retinoic acid. They also found knocking out CTBP in the APC-mutated tissue restored the function of retinoic acid.