psymberin and Lung-Neoplasms

Topics: Antineoplastic Agents; Carcinoma; Cell Line, Tumor; Cell Membrane; Cell Nucleus; Cell Survival; Coumarins; Gene Expression Regulation, Neoplastic; Humans; Intercellular Adhesion Molecule-1; Lung Neoplasms; Molecular Weight; Neoplasm Proteins; Osmolar Concentration; Protein Biosynthesis; Protein Synthesis Inhibitors; Protein Transport; Proteolysis; Receptors, Tumor Necrosis Factor, Type I; Signal Transduction

Irciniastatin A is a pederin-type marine product that potently inhibits translation. We have recently shown that irciniastatin A induces ectodomain shedding of tumor necrosis factor (TNF) receptor 1 with slower kinetics than other translation inhibitors. In human lung carcinoma A549 cells, irciniastatin A induced a marked and sustained activation of extracellular signal-regulated kinase (ERK) and induced little activation of p38 mitogen-activated protein (MAP) kinase and c-Jun N-terminal kinase (JNK). Moreover, the TNF receptor 1 shedding induced by irciniastatin A was blocked by the MAP kinase/ERK kinase inhibitor U0126, but not by the p38 MAP kinase inhibitor SB203580 or the JNK inhibitor SP600125. Thus unlike other translation inhibitors that trigger ribotoxic stress response, our results show that irciniastatin A is a unique translation inhibitor that induces a potent and sustained activation of the ERK pathway, and thereby promotes the ectodomain shedding of TNF receptor 1 in A549 cells.

Topics: Animals; Antineoplastic Agents; Biological Products; Cell Line, Tumor; Coumarins; Enzyme Inhibitors; Extracellular Signal-Regulated MAP Kinases; JNK Mitogen-Activated Protein Kinases; Lung Neoplasms; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Porifera; Receptors, Tumor Necrosis Factor; Signal Transduction; TNF Receptor-Associated Factor 1