Suppression of TGF beta-Induced Interleukin-6 Secretion by Sinulariolide from Soft Corals through Attenuation of the p38-NF-kB Pathway in Carcinoma Cells

Sinulariolide (SC-1) is a natural product extracted from the cultured-type soft coral Sinularia flexibilis and possesses anti-inflammation, anti-proliferative, and anti-migratory in several types of cancer cells. However, the molecular pathway behind its effects on inflammation remains poorly understood. Since inflammatory cytokines such as TGF beta, TNF alpha, IL-1, IL-6, and IL-8 activate transcription factors such as Smads, NF-kappa B, STAT3, Snail, Twist, and Zeb that drive the epithelial-to-mesenchymal transition (EMT), in this study, we focus on the investigation in effects of SC-1 on TGF beta-induced interleukin-6 (IL-6) releases in an in vitro cell culture model. We showed that both intracellular IL-6 expression and secretion were stimulated by TGF beta and associated with strong upregulation of IL-6 mRNA and increased transcription in A549 cells. SC-1 blocked TGF beta-induced secretion of IL-6 while showing no effect on the induction of fibronectin and plasminogen activator inhibitor-1 genes, indicating that SC-1 interferes with only a subset of TGF beta activities. In addition, SC-1 inhibits TGF beta-induced IL-6 by suppressing p38 MAPK signaling and subsequently inhibits NF-kappa B and its nuclear translocation without affecting the canonical Smad pathway and receptor turnover. Overall, these data suggest that p38 may involve in the inhibition of SC-1 in IL-6 release, thus illustrating an inhibitory effect for SC-1 in the suppression of inflammation, EMT phenotype, and tumorigenesis.