New Target for Colon Cancer Treatment

By knocking out (genetically disabling) a molecule called C-terminal binding protein (CTBP), researchers were able to save zebrafish from the effects of a mutation in the adenomatous polyposis coli (APC) gene.

In humans, mutations in this gene have long been known to trigger a series of events that cause colon polyps, which ultimately become cancerous. APC mutations play a role in 85% of colon cancers. The new findings mean CTBP also is involved in that percentage of colon cancers.

In zebrafish, APC mutations keep the intestine from developing correctly. "In essence, knocking out CTPB promotes normal development of the intestine in zebrafish carrying an APC mutation,” stated Dr. David A. Jones, a University of Utah associate professor of oncological sciences and leader of the study.

In normal cells of both humans and zebrafish, the APC gene controls the amount of CTBP present by tagging it for destruction. In tumor cells with mutated APC, CTPB is not destroyed; instead it accumulates in the cell. One function of CTBP is to inactivate the process that converts vitamin A into retinoic acid in the cell. Retinoic acid is essential in cell differentiation--the function that determines what type of cell forms and how long it lives.

This study noted that in both zebrafish and human tissues with APC mutations, there are high CTBP levels and a low capability to produce retinoic acid. In APC-mutated tissues in which CTBP had been knocked out, retinoic acid production was restored. Earlier studies in Dr. Jones' lab demonstrated that the lack of retinoic acid caused zebrafish intestines to form incorrectly, and that adding retinoic acid corrected the problems.

"Knocking out CTBP does exactly the same thing, and the logical conclusion is that it's because CTBP controls retinoic acid production,” remarked Dr. Jones. "Since CTBP is a completely new target, we must now look for potential chemical agents that would work to block its actions. That could take three to five years.”



Related Links:
Huntsman Cancer Institute