Researchers have discovered that Importin-11,
a cell nucleus import protein, is required for colorectal cancer growth and may
be a possible target for new therapies.
Researchers have identified Importin-11 as
the transporter responsible for β-catenin, a protein implicated in the
progression of many colorectal cancers, entering the cell nucleus. According to
the group, inhibiting this protein could provide a new therapy for colon
cancers.
Approximately 80 percent of colorectal
cancers are associated with mutations in the APC gene, resulting in elevated
levels of β-catenin. Increased β-catenin levels are followed by the
accumulation of the protein in the cell nucleus, where it can activate numerous
genes that drive cell proliferation and promote the growth and maintenance of
colorectal tumours.
Until now, the method by which β-catenin
enters the cell nucleus has been poorly understood.
“Because the molecular mechanisms underlying
β-catenin nuclear transport remain unclear, we set out to identify genes
required for continuous β-catenin activity in colorectal cancer cells
harbouring APC mutations,†says Stephane Angers, a researcher of the study and
professor in the Department of Pharmaceutical Sciences at the University of
Toronto’s Leslie Dan Faculty of Pharmacy.
Angers and colleagues used CRISPR technology
to develop a new technique that allowed them to screen the human genome for
genes that support β-catenin’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.
Importin-11 was found to bind to β-catenin
and escort it into the nucleus of colorectal cancer cells. Removing Importin-11
from these cells prevented β-catenin from entering the nucleus and activating
its target genes. The researchers also discovered that Importin-11 levels are
often elevated in human colorectal cancers and that 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,†Angers says. The researchers say that learning more about how Importin-11 transports β-catenin into the nucleus may help in the development of new therapies that block this process and reduce the growth of colorectal cancers caused by mutations in APC.
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