Toronto, December 30
Researchers have found a new drug target for the treatment of colorectal cancer, in the form of a key protein that supports the growth of many types of bowel cancers.
The study, published in the Journal of Cell Biology, shows that a protein called Importin-11 transports the cancer-causing protein betacatenin 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 betacatenin levels, according to the researchers at the University of Toronto in Canada.
Around 80 per cent of colorectal cancers are associated with mutations in a gene called APC that result in elevated levels of the betacatenin protein.
This increase in betacatenin 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.
However, how betacatenin enters the cell nucleus after its levels rise is poorly understood.
“Because the molecular mechanisms underlying betacatenin nuclear transport remain unclear, we set out to identify genes required for continuous betacatenin activity in colorectal cancer cells harbouring APC mutations,” said Stephane Angers, a professor at the University of Toronto.
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 betacatenin’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.
The researchers found that Importin-11 binds to betacatenin and escorts it into the nucleus of colorectal cancer cells with mutations in APC.
Removing Importin-11 from these cells prevented betacatenin from entering the nucleus and activating its target genes.
The researchers discovered that Importin-11 levels are often elevated in human colorectal cancers.
Removing Importin-11 inhibited the growth of tumours formed by APC mutant cancer cells isolated from patients, they said.
“We conclude that Importin-11 is required for the growth of colorectal cancer cells,” Angers said.
Learning more about how Importin-11 transports betacatenin 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. PTI
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