Angiopoietin-like protein 2 renders colorectal cancer cells resistant to chemotherapy by activating spleen tyrosine kinase-phosphoinositide 3-kinase-dependent anti-apoptotic signaling.
Bottom Line: Apoptosis induced by antineoplastic drug treatment was significantly decreased in SW480/ANGPTL2 compared to control cells.Expression of anti-apoptotic BCL-2 family genes was upregulated in SW480/ANGPTL2 compared to SW480/Ctrl cells.Furthermore, ANGPTL2 increased its own expression in a feedback loop by activating the spleen tyrosine kinase-nuclear factor of activated T cells (Syk-NFAT) pathway.
Affiliation: Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.Show MeSH
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Mentions: Nuclear factor-κB induces BCL-2 family member genes(22) and is known to be activated by Syk signaling.(10) To further investigate molecular mechanisms underlying ANGPTL2 anti-apoptotic activity, we examined NF-κB activation in SW480/ANGPTL2-1 cells and SW480/Ctrl cells by staining with a p65 antibody (Fig. 4a). Analysis of staining distribution indicated that the proportion of NF-κB subunit p65 found in the nucleus increased in SW480/ANGPTL2 cells compared with control cells, which showed largely cytoplasmic staining (Fig. 4a,b). It has been reported that PI3K activates the NF-κB pathway and induces survival signals.(23) To investigate whether NF-κB activation in SW480/ANGPTL2 cells was due to activation of the PI3K pathway, we assessed p65 translocation to the nucleus in the presence of the PI3K inhibitor LY294002. Treatment of SW480/ANGPTL2-1 cells with LY294002 significantly decreased the proportion of nuclear NF-κB relative to untreated cells (Fig. 4a,c). When we asked whether Syk knockdown would alter NF-κB nuclear translocation in SW480/ANGPTL2-1 cells, we found that knockdown decreased NF-κB nuclear translocation relative to that seen in Scr control cells (Fig. S3a). Taken together, these results suggest that ANGPTL2 overexpression promotes nuclear translocation of NF-κB through the Syk–PI3K pathway in CRC cells.
Affiliation: Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.