Emerging therapeutic target in colorectal cancer
Colorectal cancer is the third most commonly occurring cancer in men and the second most commonly occurring cancer in women. As per The American Cancer Society, the lifetime risk of developing colorectal cancer is about 1 in 22 (4.49%) for men and 1 in 24 (4.15%) for women. This risk is slightly lower in women than in men. The Wnt signaling transduction pathway plays an important role in a number of developmental processes, including body axis formation, development of the central nervous system, axial specification in limb development and mouse mammary gland development.
APC gene is most commonly mutated in colorectal cancers and is assumed to be a tumor suppressor. APC binds to β-catenin which plays an important role in the Wnt signal transduction pathway. β-catenin is regulated by the APC gene, which in turn is dependent on the Wnt signal. In the absence of Wnt signal, β-catenin is free which is then bound and phosphorylated to destruction complex, phosphorylation leads to ubiquitination of β-catenin following proteolytic degradation. In the presence of Wnt signal, Wnt binds to the receptors which then leads to the deactivation of the destruction complex thus stabilizing the β-catenin and transporting it to the nucleus, which later binds to DNA binding proteins resulting in activation of transcription.
It is assumed that the APC gene controls β-catenin levels in the cell and mutation in the APC gene leads to the accumulation of β-catenin. Mutation in the APC gene deactivates the destruction complex and activates the β-catenin pathway even in the absence of Wnt signal since APC is one of the components of the destruction complex. Loss of function in the APC gene prevents the ubiquitination of β-catenin thus stabilizing it and activating the pathway.
However, how β-catenin enters the nucleus is not well understood. As per a recent study lead by Monika Mis and team which was published on December 27, 2019, in the Journal Of Cell Biology. They developed a novel and functional genomic strategy, DEADPOOL, with CRISPR gene-editing technology to study β-catenin activity in colorectal cancer cells and its increased levels due to APC mutation. One of the key genes identified was Importin-11 (IPO11), which belongs to members of the karyopherin/importin-beta family of transport receptors that mediate nucleocytoplasmic transport of protein and RNA cargoes.
Angers and colleagues discovered that Importin-11 binds to β-catenin and guides it for nuclear transport. In APC mutated colorectal cancer, it was observed that the level of β-catenin as well the level of Importin-11 were elevated. Thus removing Importin-11 from the cells would hamper β-catenin from entering the nucleus and activating the respective genes. As per the researchers, both β-catenin and Importin-11 are elevated in APC mutated colorectal cancers. Eliminating Importin-11 inhibited the formation of tumors in the cells isolated from the patients. As per the findings by Angers and colleagues, IPO11 knockout decreased colony formation of CRC cell lines and decreased proliferation of patient-derived CRC organoids.
Angers concluded that Importin-11 is required for the growth of colorectal cancer cells and obstructing β-catenin transport through Importin-11 could inhibit the growth in colorectal cancers. Discovering more about how Importin-11 transports β-catenin into the nucleus may help in the development of new therapies to block this process.
By ~ Kartik Sharma
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References
Akiyama, Tetsu. 2000. “Wnt/β-Catenin Signaling.” Cytokine & Growth Factor Reviews.
Fodde, R. 2002. “The APC Gene in Colorectal Cancer.” European Journal of Cancer 38 (7): 867–71.
https://www.cancer.org/cancer/colon-rectal-cancer/about/key-statistics.html
https://www.genengnews.com/news/novel-colon-cancer-therapeutic-target-identified/
https://www.biospace.com/article/new-target-protein-for-colorectal-cancer-identified/
https://www.eurekalert.org/pub_releases/2019-12/rup-rin121919.php
https://www.cancer.org/cancer/colon-rectal-cancer/about/key-statistics.html
https://www.wcrf.org/dietandcancer/cancer-trends/colorectal-cancer-statistics
Mis, Monika, Siobhan O’Brien, Zachary Steinhart, Sichun Lin, Traver Hart, Jason Moffat, and Stephane Angers. 2020. “IPO11 Mediates βcatenin Nuclear Import in a Subset of Colorectal Cancers.” The Journal of Cell Biology.
Plafker, S. M., and I. G. Macara. 2000. “Importin-11, a Nuclear Import Receptor for the Ubiquitin-Conjugating Enzyme, UbcM2.” The EMBO Journal 19 (20): 5502–13.
-By Kartik Sharma
