title: Morin impedes Yap nuclear translocation and fosters apoptosis through suppression of Wnt/β-catenin and NF-κB signaling in Mst1 overexpressed HepG2 cells.
abstract: 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.
authors.affiliation: Department of Biochemistry, University of Madras, Guindy Campus, Chennai 600025, Tamil Nadu, India.
authors.forename: NaveenKumar
authors.initials: N
authors.lastname: Perumal
authors.affiliation: Department of Biochemistry, University of Madras, Guindy Campus, Chennai 600025, Tamil Nadu, India; Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: MadanKumar
authors.initials: M
authors.lastname: Perumal
authors.affiliation: Department of Cellular and Molecular Biology, The University of Texas Health Science Center, Tyler, Texas, USA.
authors.forename: Anbarasu
authors.initials: A
authors.lastname: Kannan
authors.affiliation: Centre for Biotechnology, Anna University, Chennai 600025, Tamil Nadu, India.
authors.forename: Kumar
authors.initials: K
authors.lastname: Subramani
authors.affiliation: Department of Zoology, University of Madras, Guindy Campus, Chennai 600025, Tamil Nadu, India.
authors.forename: Devaraj
authors.initials: D
authors.lastname: Halagowder
authors.affiliation: Department of Biochemistry, University of Madras, Guindy Campus, Chennai 600025, Tamil Nadu, India. Electronic address: profniranjali@gmail.com.
authors.forename: NiranjaliDevaraj
authors.initials: N
authors.lastname: Sivasithamparam
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects*; D002467:Cell Nucleus / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005419:Flavonoids / Q000494:pharmacology*; D020869:Gene Expression Profiling; D056945:Hep G2 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014157:Transcription Factors; D051153:Wnt Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D000091102:YAP-Signaling Proteins; D051176:beta Catenin / Q000378:metabolism*; D047309:Flavones; D000099317:Hippo Kinases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D005419:Flavonoids; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D014157:Transcription Factors; D051153:Wnt Proteins; D000091102:YAP-Signaling Proteins; D051176:beta Catenin; C088374:YAP1 protein, human; C008548:morin; D047309:Flavones; C095566:STK4 protein, human; D000099317:Hippo Kinases
keywords: Apoptosis; Hippo signaling; Morin; Mst1; NF-κB signaling; β-catenin