An Electrophilic Analogue of Deguelin Induces p62-Mediated Autophagy in Ras-Transformed Human Mammary Epithelial Cells through Inhibition of STAT3 Signaling

Abstract

Signal transducers and activators of transcription 3 (STAT3), a member of the Janus kinase (JAK)/STAT signaling pathway, is a transcription factor that plays important roles in many aspects of cancer aggressiveness including migration, invasion, survival, self-renewal, angiogenesis, and tumor cell immune evasion by regulating the expression of multiple downstream target genes. In the previous study, a series of analogues of deguelin, a natural rotenoid present in several plants, were synthesised to develop novel STAT3 inhibitors. Among them, an electrophilic analogue SH48 bearing an α,β-unsaturated carbonyl group was found to inhibit STAT3 phosphorylation, dimerization, nuclear translocation and transcriptional activity. In this study, I confirmed the direct binding of SH48 to the STAT3 C328, C367 and C687 residues by mass spectrometric analysis. Then, I investigated the mode of SH48-induced MCF10A-RAS cell death with special focus on autophagy. p62 and STAT3 interact each other, which may facilitate the degradation of p62. SH48 inhibits interaction between p62 and STAT3, thereby maintaining the stability of p62 in MCF10A-RAS cells. In conclusion, the deguelin analogue SH48 inhibits STAT3 signaling by direct interaction with the C328, C367 and C687 residues of STAT3.