Isomalabaricanes are a small class of rearranged
triterpenoids obtained from marine sponges. Most of these are cytotoxic to
tumor cells, but the underlying mechanism is not clear. In this study, it was demonstrated that
stellettin A (1), obtained from Geodia japonica, inhibited the growth of B16F10 murine
melanoma cells by the induction of endoplasmic reticulum stress and accumulation of unfolded
proteins. Immunoblotting analysis revealed abnormal glycosylation patterns of two
melanoma marker
proteins,
tyrosinase and
tyrosinase-related
protein 1, and the retention of these
proteins in the endoplasmic reticulum. Compound 1 induced the upregulation of the unfolded
protein chaperone,
glucose-regulated
protein 78, in a dose-dependent manner. Increase of autophagosome-associated
protein light chain 3 (LC3) in a membrane-bound form (LC3II) and its immunofluorescence co-localization with
tyrosinase suggest the possible removal of deglycosylated and unfolded
proteins by autophagy of the cells. There was no change in either the expression of the apoptosis marker
protein Bcl-2 or the appearance of apoptotic nuclei in 1-treated cells. Taken together, 1 is an endoplasmic reticulum stressor that inhibits the growth of
B16 melanoma cells by induction of abnormal protein glycosylation and autophagy.