Researchers From University of Toronto Discover New Therapeutic Target For Bowel/Colorectal Cancer.
Source: Thailand Medical News Dec 28, 2019 5 years, 2 days, 22 hours, 43 minutes ago
Medical researchers from the
University of Toronto have identified a key protein that supports the growth of many
colorectal cancers. The study, which is published in the
Journal of Cell Biology, reveals that a protein called
Importin-11 transports the
cancer-causing protein
βcatenin 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
βcatenin levels.
Roughly about 80% of
colorectal cancers are associated with mutations in a gene called
APC that result in elevated levels of the
βcatenin protein. This increase in
βcatenin 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 tumors. But how
βcatenin enters the cell nucleus after its levels rise is poorly understood.
Dr Stephane Angers, a Professor in the Department of Pharmaceutical Sciences at the University of Toronto's Leslie Dan Faculty of Pharmacy told
Thailand Medical News, "Because the molecular mechanisms underlying
βcatenin nuclear transport remain unclear, we set out to identify genes required for continuous
βcatenin activity in
colorectal cancer cells harboring
APC mutations."
Utilizing
CRISPR DNA editing technology, Dr Angers and colleagues, including graduate student Monika Mis, developed a new technique that allowed them to screen the human genome for genes that support
βcatenin'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.
Dr Angers and colleagues found that
Importin-11 binds to
βcatenin and escorts it into the nucleus of
colorectal cancer cells with mutations in
APC. Removing Importin-11 from these cells prevented
βcatenin from entering the nucleus and activating its target genes.
The medical researchers discovered that
Importin-11 levels are often elevated in human
colorectal cancers. Moreover, removing
Importin-11 inhib
ited the growth of tumors formed by
APC mutant
cancer cells isolated from patients.
Dr Angers added, "We conclude that
Importin-11 is required for the growth of
colorectal cancer cells. Learning more about how I
mportin-11 transports
βcatenin 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.”
Reference: PO11 mediates βcatenin nuclear import in a subset of colorectal cancers
Monika Mis, Siobhan O’Brien, Zachary Steinhart, Sichun Lin, Traver Hart, Jason Moffat, Stephane Angers J Cell Biol (2020) 219 (2): e201903017. DOI: 10.1083/jcb.201903017
https://doi.org/10.1083/jcb.201903017
