Honaucin A, mechanism of action and role as a potential cancer prevention agent

Abstract

Three related natural products, the honaucins A-C, were isolated from a cyanobacterium overgrowing a coral reef in Hawaii. Subsequent biological investigations revealed that these molecules inhibit both prokaryotic quorum sensing and eukaryotic inflammation. The honaucins were originally identified as molecules of interest in an in vitro assay that quantified their ability to attenuate nitric oxide production in LPS-stimulated macrophages. Continued experiments using honaucin A displayed a transcriptional down-regulation of IL-6, TNFα, IL-1β, and iNOS in these cells, as well as in vivo anti-inflammatory activity in a murine model of ear edema. To uncover the mechanism of action of honaucin A, RNA deep sequencing was performed using total RNA from honaucin A-treated macrophages. Analysis of differentially regulated transcripts strongly suggests that honaucin A is an activator of a pathway of cytoprotective genes. This signaling pathway has recently drawn interest for its potential application in the treatment of neurodegenerative and autoimmune diseases, as well as cancer. Experiments involving reporter assays and protein pull down using a biotinylated probe to validate the proposed target will be discussed.