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: Syk reportedly activates NFAT signaling.(25) In addition, we previously reported that NFATc induces ANGPTL2 expression in tumor cells.(10) These findings suggest that ANGPTL2 increases its own expression through Syk–NFAT signaling. To examine this possibility, we evaluated transcript levels of NFATc family genes in SW480/ANGPTL2-1 or SW480/Ctrl cells by real-time PCR. Our analysis showed that SW480 cells express NFATc3 mRNA rather than other NFATcs (Fig. 5a). In normal conditions, inactive NFATc proteins are cytoplasmic.(26) When cells are activated, intracellular Ca2+ concentrations increase and NFATc proteins move to the nucleus to activate target genes, including ANGPTL2.(9) Therefore, we examined intracellular localization of NFATc3 in SW480/ANGPTL2-1 or SW480/Ctrl cells. NFATc3 nuclear staining was more apparent in SW480/ANGPTL2 cells compared to control cells (Fig. 5b), suggesting that NFATc3 is activated in ANGPTL2-overexpressing cells.
Affiliation: Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.