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: The BCL-2 family is a key regulator of programmed cell death.(11) It is comprised of both pro- and anti-apoptotic proteins, and the latter (BCL-2, BCL-XL and MCL-1) reportedly inhibit 5-FU-induced apoptosis in CRC cells.(19) Therefore, we examined the expression of BCL-2 family mRNAs in SW480/ANGPTL2-1 and -2 cells or SW480/Ctrl cells. Real-time PCR and Western blot analyses revealed upregulated expression of anti-apoptotic BCL-2 and BCL-XL in SW480/ANGPTL2-1 and -2 cells relative to SW480/Ctrl cells; however, we observed no significant difference in expression of MCL-1 or pro-apoptotic BAX or BAD among groups (Figs 2a,S2). Recently, several reports suggested that a high BCL-2/BAX or BCL-XL/BAX ratio is positively correlated with progression of several diseases or malignant tumors and that the BCL-2/BAX ratio may serve as a prognostic marker for patients with rectal carcinomas.(19,20) Therefore, we analyzed that ratio in SW480/ANGPTL2-1, SW480/ANGPTL2-2, and SW480/Ctrl cells and found that BCL-2/BAX and BCL-XL/BAX ratios were greater in both ANGPTL2-overexpressing lines than they were in controls (Fig. 2b).
Affiliation: Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.