Morin impedes Yap nuclear translocation and fosters apoptosis through suppression of Wnt/β-catenin and NF-κB signaling in Mst1 overexpressed HepG2 cells

• Published in: Experimental cell research 2017-06, Vol.355 (2), p.124-141
• Main Authors: Perumal, NaveenKumar, Perumal, MadanKumar, Kannan, Anbarasu, Subramani, Kumar, Halagowder, Devaraj, Sivasithamparam, NiranjaliDevaraj
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; Active Transport, Cell Nucleus - drug effects; Adaptor Proteins, Signal Transducing - metabolism; APOPTOSIS; Apoptosis - drug effects; beta Catenin - metabolism; BIOFLAVONOIDS; CARCINOGENESIS; CELL CYCLE; Cell Nucleus - metabolism; Dose-Response Relationship, Drug; Flavonoids - pharmacology; Gene Expression Profiling; Hep G2 Cells; Hippo signaling; Humans; INHIBITION; LIVER; MOLECULES; MORIN; Mst1; NEOPLASMS; NF-kappa B - metabolism; NF-κB signaling; Phosphoproteins - metabolism; PHOSPHORYLATION; PHOSPHOTRANSFERASES; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Structure-Activity Relationship; TOXICITY; Transcription Factors; TRANSLOCATION; Wnt Proteins - metabolism; Wnt Signaling Pathway - drug effects; β-catenin
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2017.03.062

Recent clinical and experimental evidences strongly acclaim Yes-associated protein (Yap), a key oncogenic driver in liver carcinogenesis, as a therapeutic target. Of the known multiple schemes to inhibit Yap activity, activation of Mammalian Sterile 20-like Kinase 1 (Mst1), an upstream regulator of Yap, appears to be a promising one. In this study, we hypothesize that morin, a bioflavonoid, mediates its anti-cancer effect through the activation of Mst1/hippo signaling in liver cancer cells. To test this hypothesis, both full length Mst1 (F-Mst1) and kinase active N-terminal Mst1 (N-Mst1)-overexpressed HepG2 cells were used. Exposure of F-Mst1 overexpressed HepG2 cells to morin activated Mst1 by caspase-3 cleavage and thereby inhibited Yap nuclear translocation and fostered apoptosis. Morin suppressed NF-κB p65 and Wnt/β-catenin signaling through Mst1 activation via cleavage and phosphorylation, leading to cell death. Annexin-V/PI staining further confirmed the induction of apoptosis in morin treated F-Mst1 overexpressed cells. The present study shows that morin targets cell survival molecules such as NF-κB p65 and β-catenin through activation of hippo signaling. Therefore, morin could be considered as a potential anti-cancer agent against liver cancer. [Display omitted] •Morin induced cytotoxicity in cultured HepG2 cells.•Morin activated hippo pathway via Mst1 activation in transfected HepG2 cells.•Morin suppressed Wnt/β-catenin signaling and induced G0/G1 cell cycle arrest.•Morin inhibited NF-κB signaling through Mst1 activation in transfected HepG2 cells.•Morin potentiates apoptosis through Mst1-JNK-caspase mediated mechanism in HepG2 cells.