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Lack of Stem Cell Regulator Leads to Intestinal Cancer in Mouse Model

By LabMedica International staff writers
Posted on 15 Feb 2015
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Image: PKC-zeta intestinal cancer stem cell regulation (Photo courtesy of Sanford-Burnham Medical Research Institute).
Image: PKC-zeta intestinal cancer stem cell regulation (Photo courtesy of Sanford-Burnham Medical Research Institute).
The interaction of the enzyme protein kinase C-zeta (PKC-zeta) with the enzymes Yap and beta-catenin was found to be a key regulator of intestinal stem cell function and the point where normal cell replacement could give rise to cancerous growth.

PKC-zeta is a member of the PKC family of serine/threonine kinases that are involved in a variety of cellular processes such as proliferation, differentiation, and secretion. Unlike the classical PKC isoenzymes that are calcium-dependent, PKC-zeta exhibits a kinase activity that is independent of calcium and diacylglycerol but not of phosphatidylserine. Furthermore, it is insensitive to typical PKC inhibitors and cannot be activated by phorbol ester.

Investigators at the Sanford-Burnham Medical Research Institute (La Jolla, CA, USA) employed a genetically engineered mouse model for intestinal cancer to study how regulation of homeostasis in intestinal epithelial stem cells could derail and lead to tumor development.

They reported in the February 5, 2015, online edition of the journal Cell Reports that PKC-zeta suppressed intestinal stem cell function by promoting the downregulation of beta-catenin and Yap through direct phosphorylation.

Yap is a transcriptional co-activator and its proliferative and oncogenic activity is driven by its association with the TEAD family of transcription factors, which up-regulate genes that promote cell growth and inhibit apoptosis. Beta-catenin is part of a complex of proteins that constitute adherens junctions (AJs). AJs are necessary for the creation and maintenance of epithelial cell layers by regulating cell growth and adhesion between cells. Beta-catenin also anchors the actin cytoskeleton and may be responsible for transmitting the contact inhibition signal that causes cells to stop dividing once the epithelial sheet is complete. An increase in beta-catenin production has been noted in those people with basal cell carcinoma and leads to the increase in proliferation of related tumors.

The investigators found that PKC-zeta deficiency with a concomitant rise in Yap and beta-catenin activity resulted in increased stem cell activity in organoid cultures and in vivo, accounting for the increased tumorigenic and regenerative action in the PKC-zeta-deficient mice.

“Accumulating evidence suggests that cancer stem cells are responsible for cancer initiation, progression, metastasis, recurrence, and drug resistance,” said senior author Dr. Jorge Moscat, director of the cell death and survival networks program at the Sanford-Burnham Medical Research Institute. “Our new research provides a better understanding of the signaling cascades that regulate stem cells and is essential for the design of new and more-efficacious therapies for cancer. Our results offer new possibilities for the prevention and treatment of intestinal cancers by blocking the pathways that lead to tumors. They also highlight a new strategy to promote intestinal regeneration after acute or chronic damage, such as that triggered by chemotherapy and radiation.”

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Sanford-Burnham Medical Research Institute



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