Betulinic acid and oleanolic acid, natural pentacyclic triterpenoids, interfere with N-linked glycan modifications to intercellular adhesion molecule-1, but not its intracellular transport to the cell surface

Abstract

Betulinic acid (3β-hydroxy-20(29)-lupen-28-oic acid), oleanolic acid (3β-hydroxy-olean-12-en-28-oic acid), and ursolic acid (3β-hydroxy-urs-12-en-28-oic acid) are close structural isomers of natural pentacyclic triterpenoid carboxylic acids. We recently identified a unique biological effect of ursolic acid, its inhibition of the intracellular trafficking of glycoproteins. In the present study, we demonstrated that betulinic acid and oleanolic acid did not inhibit the interleukin-1α-induced expression of cell-surface intercellular adhesion molecule-1 (ICAM-1) in human lung carcinoma A549 cells. Nevertheless, betulinic acid and, to a lesser extent, oleanolic acid interfered with N-linked glycan modifications to ICAM-1 in a similar manner to castanospermine (an inhibitor of endoplasmic reticulum α-glucosidases I and II), but not swainsonine (an inhibitor of Golgi α-mannosidase II). Consistent with these results, betulinic acid and oleanolic acid inhibited yeast α-glucosidase activity, but not Jack bean α-mannosidase activity. Thus, to the best of our knowledge, this is the first study to show that betulinic acid and oleanolic acid interfere with N-linked glycan modifications to ICAM-1, but not its intracellular transport to the cell surface.