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Ursolic acid, a natural pentacyclic triterpenoid, inhibits intracellular trafficking of proteins and induces accumulation of intercellular adhesion molecule-1 linked to high-mannose-type glycans in the endoplasmic reticulum.

Mitsuda S, Yokomichi T, Yokoigawa J, Kataoka T - FEBS Open Bio (2014)

Bottom Line: By contrast, ursolic acid exerted weak inhibitory effects on the IL-1α-induced ICAM-1 expression at the protein level.Surprisingly, we found that ursolic acid decreased the apparent molecular weight of ICAM-1 and altered the structures of N-linked oligosaccharides bound to ICAM-1.Thus, our results reveal that ursolic acid inhibits intracellular trafficking of proteins and induces the accumulation of ICAM-1 linked to high-mannose-type glycans in the endoplasmic reticulum.

View Article: PubMed Central - PubMed

Affiliation: Department of Applied Biology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan.

ABSTRACT
Ursolic acid (3β-hydroxy-urs-12-en-28-oic acid) is a natural pentacyclic triterpenoid that is present in many plants, including medicinal herbs, and foods. Ursolic acid was initially identified as an inhibitor of the expression of intercellular adhesion molecule-1 (ICAM-1) in response to interleukin-1α (IL-1α). We report here a novel biological activity: ursolic acid inhibits intracellular trafficking of proteins. Ursolic acid markedly inhibited the IL-1α-induced cell-surface ICAM-1 expression in human cancer cell lines and human umbilical vein endothelial cells. By contrast, ursolic acid exerted weak inhibitory effects on the IL-1α-induced ICAM-1 expression at the protein level. Surprisingly, we found that ursolic acid decreased the apparent molecular weight of ICAM-1 and altered the structures of N-linked oligosaccharides bound to ICAM-1. Ursolic acid induced the accumulation of ICAM-1 in the endoplasmic reticulum, which was linked mainly to high-mannose-type glycans. Moreover, in ursolic-acid-treated cells, the Golgi apparatus was fragmented into pieces and distributed over the cells. Thus, our results reveal that ursolic acid inhibits intracellular trafficking of proteins and induces the accumulation of ICAM-1 linked to high-mannose-type glycans in the endoplasmic reticulum.

No MeSH data available.


Related in: MedlinePlus

Ursolic acid does not inhibit IL-1α-induced expression of ICAM-1 at the protein level but affects its post-translational modification. A549 cells (A), MCF-7 cells (B), and HUVEC (C) were preincubated with various concentrations of ursolic acid for 1 h and then incubated with IL-1α (0.25 ng/ml) for 6 h. Cell lysates were analyzed by Western blotting. Data are representative of at least three independent experiments for A549 cells and MCF-7 cells and two independent experiments for HUVEC.
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f0010: Ursolic acid does not inhibit IL-1α-induced expression of ICAM-1 at the protein level but affects its post-translational modification. A549 cells (A), MCF-7 cells (B), and HUVEC (C) were preincubated with various concentrations of ursolic acid for 1 h and then incubated with IL-1α (0.25 ng/ml) for 6 h. Cell lysates were analyzed by Western blotting. Data are representative of at least three independent experiments for A549 cells and MCF-7 cells and two independent experiments for HUVEC.

Mentions: We next investigated the effect of ursolic acid on the NF-κB signaling pathway induced by IL-1 receptor. Ursolic acid slightly augmented the IL-1α-induced translocation of NF-κB subunits, p65 and p50, from the cytoplasm to the nucleus in A549 cells (Fig. S2). These data suggested that ursolic acid inhibits cell-surface ICAM-1 expression at the steps downstream of NF-κB activation. We therefore examine the effect of ursolic acid on ICAM-1 expression at the protein level by Western blotting. ICAM-1 was detected as multiple bands migrating to more than 80 kDa in A549 cells stimulated with IL-1α (Fig. 2A). Unexpectedly, we found that ursolic acid weakly affected the total amount of ICAM-1 but decreased the molecular weight of ICAM-1 to 60–70 kDa in A549 cells (Fig. 2A). In MCF-7 cells and normal human umbilical vein endothelial cells (HUVEC), ursolic acid also decreased the molecular weight of ICAM-1 to values similar to those observed in A549 cells (Fig. 2B and C). In addition, ursolic acid decreased the molecular weights of E-selectin and VCAM-1 in HUVEC (Fig. 2C). These results indicate that ursolic acid marginally reduces the IL-1α-induced protein synthesis of ICAM-1 but affects the post-translational modification of ICAM-1.


Ursolic acid, a natural pentacyclic triterpenoid, inhibits intracellular trafficking of proteins and induces accumulation of intercellular adhesion molecule-1 linked to high-mannose-type glycans in the endoplasmic reticulum.

Mitsuda S, Yokomichi T, Yokoigawa J, Kataoka T - FEBS Open Bio (2014)

Ursolic acid does not inhibit IL-1α-induced expression of ICAM-1 at the protein level but affects its post-translational modification. A549 cells (A), MCF-7 cells (B), and HUVEC (C) were preincubated with various concentrations of ursolic acid for 1 h and then incubated with IL-1α (0.25 ng/ml) for 6 h. Cell lysates were analyzed by Western blotting. Data are representative of at least three independent experiments for A549 cells and MCF-7 cells and two independent experiments for HUVEC.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3958921&req=5

f0010: Ursolic acid does not inhibit IL-1α-induced expression of ICAM-1 at the protein level but affects its post-translational modification. A549 cells (A), MCF-7 cells (B), and HUVEC (C) were preincubated with various concentrations of ursolic acid for 1 h and then incubated with IL-1α (0.25 ng/ml) for 6 h. Cell lysates were analyzed by Western blotting. Data are representative of at least three independent experiments for A549 cells and MCF-7 cells and two independent experiments for HUVEC.
Mentions: We next investigated the effect of ursolic acid on the NF-κB signaling pathway induced by IL-1 receptor. Ursolic acid slightly augmented the IL-1α-induced translocation of NF-κB subunits, p65 and p50, from the cytoplasm to the nucleus in A549 cells (Fig. S2). These data suggested that ursolic acid inhibits cell-surface ICAM-1 expression at the steps downstream of NF-κB activation. We therefore examine the effect of ursolic acid on ICAM-1 expression at the protein level by Western blotting. ICAM-1 was detected as multiple bands migrating to more than 80 kDa in A549 cells stimulated with IL-1α (Fig. 2A). Unexpectedly, we found that ursolic acid weakly affected the total amount of ICAM-1 but decreased the molecular weight of ICAM-1 to 60–70 kDa in A549 cells (Fig. 2A). In MCF-7 cells and normal human umbilical vein endothelial cells (HUVEC), ursolic acid also decreased the molecular weight of ICAM-1 to values similar to those observed in A549 cells (Fig. 2B and C). In addition, ursolic acid decreased the molecular weights of E-selectin and VCAM-1 in HUVEC (Fig. 2C). These results indicate that ursolic acid marginally reduces the IL-1α-induced protein synthesis of ICAM-1 but affects the post-translational modification of ICAM-1.

Bottom Line: By contrast, ursolic acid exerted weak inhibitory effects on the IL-1α-induced ICAM-1 expression at the protein level.Surprisingly, we found that ursolic acid decreased the apparent molecular weight of ICAM-1 and altered the structures of N-linked oligosaccharides bound to ICAM-1.Thus, our results reveal that ursolic acid inhibits intracellular trafficking of proteins and induces the accumulation of ICAM-1 linked to high-mannose-type glycans in the endoplasmic reticulum.

View Article: PubMed Central - PubMed

Affiliation: Department of Applied Biology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan.

ABSTRACT
Ursolic acid (3β-hydroxy-urs-12-en-28-oic acid) is a natural pentacyclic triterpenoid that is present in many plants, including medicinal herbs, and foods. Ursolic acid was initially identified as an inhibitor of the expression of intercellular adhesion molecule-1 (ICAM-1) in response to interleukin-1α (IL-1α). We report here a novel biological activity: ursolic acid inhibits intracellular trafficking of proteins. Ursolic acid markedly inhibited the IL-1α-induced cell-surface ICAM-1 expression in human cancer cell lines and human umbilical vein endothelial cells. By contrast, ursolic acid exerted weak inhibitory effects on the IL-1α-induced ICAM-1 expression at the protein level. Surprisingly, we found that ursolic acid decreased the apparent molecular weight of ICAM-1 and altered the structures of N-linked oligosaccharides bound to ICAM-1. Ursolic acid induced the accumulation of ICAM-1 in the endoplasmic reticulum, which was linked mainly to high-mannose-type glycans. Moreover, in ursolic-acid-treated cells, the Golgi apparatus was fragmented into pieces and distributed over the cells. Thus, our results reveal that ursolic acid inhibits intracellular trafficking of proteins and induces the accumulation of ICAM-1 linked to high-mannose-type glycans in the endoplasmic reticulum.

No MeSH data available.


Related in: MedlinePlus