Inhibition of protein synthesis and activation of stress-activated protein kinases by onnamide A and theopederin B, antitumor marine natural products

During the course of screening for the agents that activate transforming growth factor-beta (TGF-beta) signaling cascade, onnamide A and theopederin B, heterocyclic compounds related to mycalamides from a marine sponge, were found to induce plasminogen activator inhibitor-1 (PAI-1) promoter-derived gene expression in Mv1Lu cells. The maximum induction of the PAI-1 promoter by onnamide A and theopederin B was observed at the concentrations of 50 nM and 2 nM, respectively. These compounds strongly inhibited protein synthesis at the 50% inhibitory concentrations of 30 nM for onnamicle A and 1.9 nM for theopeclerin B, and induced activation of p38 mitogen-activated protein kinase and c-Jun NH2-terminal protein kinase (JNK). Anisomycin, a well-known inducer of ribotoxic stress that inhibits protein synthesis and activates both p38 kinase and JNK, also activated PAI-1 gene expression. Furthermore, PAI-1 expression by onnamide A, theopeclerin B, and anisomycin was inhibited by SB202190 and SP600125, specific inhibitors of stress-activated protein kinases. Onnamide A and theopeclerin B were cytotoxic to a variety of cell lines and strongly induced apoptosis in HeLa cells within 24 h, which was accompanied by the sustained activation of p38 kinase and JNK. These results suggest that onnamide A and theopedirin B trigger a ribotoxic stress-like response, thereby inducing p38 kinase and JNK activation, the kinase-dependent PAI-1 gene expression, and apoptosis.