Researchers identify key protein that supports growth of many colorectal cancers

Researchers have identified a key protein that supports the growth of many colorectal cancers, also known as bowel cancers.

The study reveals that a protein called Importin-11 transports the cancer-causing protein bcatenin into the nucleus of colon cancer cells, where it can drive cell proliferation. Inhibiting this transport step could block the growth of most colorectal cancers caused by elevated bcatenin levels.

The study was published in the journal of Cell Biology.

Around 80 per cent of colorectal cancers are associated with mutations in a gene called APC that result in elevated levels of the bcatenin protein.

This increase in bcatenin is followed by the protein's accumulation in the cell nucleus, where it can activate numerous genes that drive cell proliferation and promote the growth and maintenance of colorectal tumours.

 

But how bcatenin enters the cell nucleus after its levels rise is poorly understood.

"Because the molecular mechanisms underlying bcatenin nuclear transport remain unclear, we set out to identify genes required for continuous bcatenin activity in colorectal cancer cells harbouring APC mutations," says Stephane Angers, a professor at the Department of Pharmaceutical Sciences, the University of Toronto's Leslie Dan Faculty of Pharmacy.

Using CRISPR DNA editing technology, Angers and colleagues, including graduate student Monika Mis, developed a new technique that allowed them to screen the human genome for genes that support bcatenin's activity in colorectal cancer cells after its levels have been elevated by mutations in APC.

One of the main genes they identified was IPO11, which encodes a protein called Importin-11 that is known to be involved in nuclear import.

Angers and colleagues found that Importin-11 binds to bcatenin and escorts it into the nucleus of colorectal cancer cells with mutations in APC. Removing Importin-11 from these cells prevented bcatenin from entering the nucleus and activating its target genes.

The researchers discovered that Importin-11 levels are often elevated in human colorectal cancers. Moreover, removing Importin-11 inhibited the growth of tumours formed by APC mutant cancer cells isolated from patients.

"We conclude that Importin-11 is required for the growth of colorectal cancer cells," adds Angers says.

Learning more about how Importin-11 transports bcatenin into the nucleus may help researchers develop new therapies that block this process and reduce the growth of colorectal cancers caused by mutations in APC.