Identification of Hoiamide A as an Inducer of Oxidative and Endoplasmic Reticulum Secretory Pathway Stress

The endoplasmic reticulum (ER) to Golgi secretory compartment of eukaryotic cells is highly sensitive to changes in intracellular homeostasis. Using a primary screening assay that monitors the function of this pathway, we prioritized a cyanobacterial extract from the Red Sea that decreased secretion of a bioluminescent reporter, Gaussia luciferase (GLuc), in living cells. A comparison of LCMS2 data against the GNPS database revealed a match for macrocyclic depsipeptide hoiamide A (1). Biological testing confirmed the ability of 1 to induce a mixed, non-lethal stress response in human U87-MG glioblastoma cells; analysis of stress markers by qRT-PCR revealed early upregulation of superoxide dismutase 1 (SOD1) and C/EBP-homologous protein (CHOP) relative to the control. Co-treatment of cells with 1 (100 nM to 3 μM) and antioxidant N-acetylcysteine afforded full protection from 1-induced decreases in GLuc secretion. We report that terminally differentiated human SH-SY5Y neuroblastoma cells, with a neuron-like phenotype, are highly sensitive to nanomolar concentrations of 1, whereas undifferentiated cells remained viable at 3 μM. These results expand the known biology of hoiamides and suggest that neurotoxic potential of 1 is likely due to an inherent failure of neurons to adapt to the loss of redox homeostasis and sustained ER stress.