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Angiopoietin-like protein 2 renders colorectal cancer cells resistant to chemotherapy by activating spleen tyrosine kinase-phosphoinositide 3-kinase-dependent anti-apoptotic signaling.

Horiguchi H, Endo M, Miyamoto Y, Sakamoto Y, Odagiri H, Masuda T, Kadomatsu T, Tanoue H, Motokawa I, Terada K, Morioka MS, Manabe I, Baba H, Oike Y - Cancer Sci. (2014)

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.To assess signaling downstream of ANGPTL2 underlying this effect, we carried out RNA sequencing analysis of SW480/ANGPTL2 and SW480/Ctrl cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.

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Angiopoietin-like protein 2 (ANGPTL2) positively regulates itself by activating the spleen tyrosine kinase–nuclear factor of activated T cells (Syk–NFAT) pathway in colorectal cancer cells. (a) Relative mRNA expression of NFAT family members in SW480/Ctrl, SW480/ANGPTL2-1, or SW480/ANGPTL2-2 cells (n = 3). (b) Nuclear translocation of NFATc3 in SW480/Ctrl or SW480/ANGPTL2-1 cells. Nuclei were counterstained with DAPI. Arrowheads indicate overlap of NFATc3 and DAPI staining. Scale bar = 50 μm. (c) Relative expression of endogenous ANGPTL2 mRNA in SW480/Ctrl or SW480/ANGPTL2-1 cells, either non-treated (control) or treated with the NFAT inhibitor cyclosporin A (CsA) (n = 3). Data from non-treated SW480/Ctrl cells was set at 1. Error bars show SEM. **P < 0.01.
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fig05: Angiopoietin-like protein 2 (ANGPTL2) positively regulates itself by activating the spleen tyrosine kinase–nuclear factor of activated T cells (Syk–NFAT) pathway in colorectal cancer cells. (a) Relative mRNA expression of NFAT family members in SW480/Ctrl, SW480/ANGPTL2-1, or SW480/ANGPTL2-2 cells (n = 3). (b) Nuclear translocation of NFATc3 in SW480/Ctrl or SW480/ANGPTL2-1 cells. Nuclei were counterstained with DAPI. Arrowheads indicate overlap of NFATc3 and DAPI staining. Scale bar = 50 μm. (c) Relative expression of endogenous ANGPTL2 mRNA in SW480/Ctrl or SW480/ANGPTL2-1 cells, either non-treated (control) or treated with the NFAT inhibitor cyclosporin A (CsA) (n = 3). Data from non-treated SW480/Ctrl cells was set at 1. Error bars show SEM. **P < 0.01.

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.


Angiopoietin-like protein 2 renders colorectal cancer cells resistant to chemotherapy by activating spleen tyrosine kinase-phosphoinositide 3-kinase-dependent anti-apoptotic signaling.

Horiguchi H, Endo M, Miyamoto Y, Sakamoto Y, Odagiri H, Masuda T, Kadomatsu T, Tanoue H, Motokawa I, Terada K, Morioka MS, Manabe I, Baba H, Oike Y - Cancer Sci. (2014)

Angiopoietin-like protein 2 (ANGPTL2) positively regulates itself by activating the spleen tyrosine kinase–nuclear factor of activated T cells (Syk–NFAT) pathway in colorectal cancer cells. (a) Relative mRNA expression of NFAT family members in SW480/Ctrl, SW480/ANGPTL2-1, or SW480/ANGPTL2-2 cells (n = 3). (b) Nuclear translocation of NFATc3 in SW480/Ctrl or SW480/ANGPTL2-1 cells. Nuclei were counterstained with DAPI. Arrowheads indicate overlap of NFATc3 and DAPI staining. Scale bar = 50 μm. (c) Relative expression of endogenous ANGPTL2 mRNA in SW480/Ctrl or SW480/ANGPTL2-1 cells, either non-treated (control) or treated with the NFAT inhibitor cyclosporin A (CsA) (n = 3). Data from non-treated SW480/Ctrl cells was set at 1. Error bars show SEM. **P < 0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4317964&req=5

fig05: Angiopoietin-like protein 2 (ANGPTL2) positively regulates itself by activating the spleen tyrosine kinase–nuclear factor of activated T cells (Syk–NFAT) pathway in colorectal cancer cells. (a) Relative mRNA expression of NFAT family members in SW480/Ctrl, SW480/ANGPTL2-1, or SW480/ANGPTL2-2 cells (n = 3). (b) Nuclear translocation of NFATc3 in SW480/Ctrl or SW480/ANGPTL2-1 cells. Nuclei were counterstained with DAPI. Arrowheads indicate overlap of NFATc3 and DAPI staining. Scale bar = 50 μm. (c) Relative expression of endogenous ANGPTL2 mRNA in SW480/Ctrl or SW480/ANGPTL2-1 cells, either non-treated (control) or treated with the NFAT inhibitor cyclosporin A (CsA) (n = 3). Data from non-treated SW480/Ctrl cells was set at 1. Error bars show SEM. **P < 0.01.
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.

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.To assess signaling downstream of ANGPTL2 underlying this effect, we carried out RNA sequencing analysis of SW480/ANGPTL2 and SW480/Ctrl cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.

Show MeSH
Related in: MedlinePlus