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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. - Highlights: • Morin induced cytotoxicity in cultured HepG2 cells. • Morin activated hippo pathway via Mst1 activation in transfected HepG2more » 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.« less

Authors:
 [1];  [1];  [2];  [3];  [4];  [5];  [1]
  1. Department of Biochemistry, University of Madras, Guindy Campus, Chennai 600025, Tamil Nadu (India)
  2. (United States)
  3. Department of Cellular and Molecular Biology, The University of Texas Health Science Center, Tyler, Texas (United States)
  4. Centre for Biotechnology, Anna University, Chennai 600025, Tamil Nadu (India)
  5. Department of Zoology, University of Madras, Guindy Campus, Chennai 600025, Tamil Nadu (India)
Publication Date:
OSTI Identifier:
22649860
Resource Type:
Journal Article
Resource Relation:
Journal Name: Experimental Cell Research; Journal Volume: 355; Journal Issue: 2; Other Information: Copyright (c) 2017 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; APOPTOSIS; BIOFLAVONOIDS; CARCINOGENESIS; CELL CYCLE; INHIBITION; LIVER; MOLECULES; MORIN; NEOPLASMS; PHOSPHORYLATION; PHOSPHOTRANSFERASES; TOXICITY; TRANSLOCATION

Citation Formats

Perumal, NaveenKumar, Perumal, MadanKumar, Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, Kannan, Anbarasu, Subramani, Kumar, Halagowder, Devaraj, and Sivasithamparam, NiranjaliDevaraj, E-mail: profniranjali@gmail.com. Morin impedes Yap nuclear translocation and fosters apoptosis through suppression of Wnt/β-catenin and NF-κB signaling in Mst1 overexpressed HepG2 cells. United States: N. p., 2017. Web. doi:10.1016/J.YEXCR.2017.03.062.
Perumal, NaveenKumar, Perumal, MadanKumar, Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, Kannan, Anbarasu, Subramani, Kumar, Halagowder, Devaraj, & Sivasithamparam, NiranjaliDevaraj, E-mail: profniranjali@gmail.com. Morin impedes Yap nuclear translocation and fosters apoptosis through suppression of Wnt/β-catenin and NF-κB signaling in Mst1 overexpressed HepG2 cells. United States. doi:10.1016/J.YEXCR.2017.03.062.
Perumal, NaveenKumar, Perumal, MadanKumar, Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, Kannan, Anbarasu, Subramani, Kumar, Halagowder, Devaraj, and Sivasithamparam, NiranjaliDevaraj, E-mail: profniranjali@gmail.com. Thu . "Morin impedes Yap nuclear translocation and fosters apoptosis through suppression of Wnt/β-catenin and NF-κB signaling in Mst1 overexpressed HepG2 cells". United States. doi:10.1016/J.YEXCR.2017.03.062.
@article{osti_22649860,
title = {Morin impedes Yap nuclear translocation and fosters apoptosis through suppression of Wnt/β-catenin and NF-κB signaling in Mst1 overexpressed HepG2 cells},
author = {Perumal, NaveenKumar and Perumal, MadanKumar and Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390 and Kannan, Anbarasu and Subramani, Kumar and Halagowder, Devaraj and Sivasithamparam, NiranjaliDevaraj, E-mail: profniranjali@gmail.com},
abstractNote = {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. - Highlights: • 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.},
doi = {10.1016/J.YEXCR.2017.03.062},
journal = {Experimental Cell Research},
number = 2,
volume = 355,
place = {United States},
year = {Thu Jun 15 00:00:00 EDT 2017},
month = {Thu Jun 15 00:00:00 EDT 2017}
}