Mechanism Explains How Colon Cancer Suppressor Protein Works

The intracellular protein NLRC3 (NLR family CARD domain containing 3) blocks growth of colon cancer by suppressing activation of mTOR (Mechanistic target of rapamycin) signaling pathways.

NLRs (nucleotide-binding domain and leucine-rich repeats) belong to a large family of cytoplasmic sensors that regulate a diverse range of biological functions. One of these functions is to contribute to immunity against infectious diseases, but dysregulation of their functional activity leads to the development of inflammatory and autoimmune diseases. NLRC3 is a poorly characterized member of the NLR family and was identified in a genomic screen for genes encoding proteins bearing leucine-rich repeats (LRRs) and nucleotide-binding domains. Expression of NLRC3 was drastically reduced in the tumor tissue of patients with colorectal cancer compared to healthy tissues, highlighting an undefined potential function for this sensor in the development of cancer.

To learn more about a possible link between NLRC3 and colon cancer, investigators at St. Jude Children's Research Hospital (Memphis, TN, USA) worked with various mouse colon cancer models including those deficient or lacking in NLRC3.

The investigators reported in the December 12, 2016, online edition of the journal Nature that mice lacking NLRC3 were hyper-susceptible to colitis and development of colorectal tumors. A mouse strain with a tendency to develop colon polyps showed much greater tumor development when they lacked NLRC3, and overexpression of NLRC3 blocked tumor formation. The effect of NLRC3 was most dominant in enterocytes, in which it suppressed activation of the mTOR signaling pathways and inhibited cellular proliferation and stem-cell-derived organoid formation. NLRC3 associated with PI3K (Phosphoinositide 3-kinase) and blocked activation of the PI3K-dependent kinase AKT (Protein kinase B) following binding of growth factor receptors or Toll-like receptor 4.

"All of these complementary approaches to understanding NLRC3 allowed us to really nail it down that NLRC3 is important for protecting from abnormal colon cell growth, and when it is not present, tumors will develop," said senior author Dr. Kanneganti Thirumala-Devi, an immunologist at St. Jude Children's Research Hospital. "This suggested that if we can somehow induce NLRC3 expression clinically, it will block the signaling pathways that lead to tumorigenesis. In developing drug therapies, it might be difficult to target the PI3K-mTOR pathway itself, because it is such a central node in cell signaling. Thus, we could target NLRC3 itself and block tumorigenesis early on."

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