The direct STAT3 inhibitor 6-ethoxydihydrosanguinarine exhibits anticancer activity in gastric cancer

Abstract

Signal transducer and activator of transcription 3 (STAT3) plays a key role in promoting tumor malignant progression. Suppression of hyperactivated STAT3 signaling has emerged as a potential therapeutic strategy for many cancer types. In this study, the effect of 6-ethoxydihydrosanguinarine (6-EDS), a secondary transformation product formed from dihydrosanguinarine, isolated from Macleaya (Papaveraceae), was evaluated in gastric cancer (GC). We demonstrated that 6-EDS inhibited the survival, migration, and invasiveness of GC cells in vitro. Moreover, 6-EDS inhibited STAT3 phosphorylation and transcriptional activity, thus suppressing the mRNA expression of downstream target genes associated with the malignant survival, migration, and invasiveness of GC cells. Molecular docking indicated that 6-EDS directly bound the SH2 domain of STAT3. Molecular dynamics simulations suggested that 6-EDS inhibited the binding of phosphorylated and non-phosphorylated STAT3 to target DNA. Cellular thermal-shift assays and microscale thermophoresis further confirmed the direct binding of 6-EDS to STAT3. Site-directed mutagenesis indicated that the S611 residue in the SH2 domain of STAT3 is critical for 6-EDS binding. In vivo, 6-EDS decreased tumor growth in xenografted nude mice by blocking STAT3 signaling. These findings indicated that 6-EDS, a direct STAT3 inhibitor, may be a potent anticancer candidate for GC therapy.