Transglutaminase is a mesothelioma cancer stem cell survival protein that is required for tumor formation

Abstract

// Gautam Adhikary 1 , Daniel Grun 1 , H. Richard Alexander 7 , Joseph S. Friedberg 4, 5 , Wen Xu 1 , Jeffrey W. Keillor 6 , Sivaveera Kandasamy 5 and Richard L. Eckert 1, 2, 3, 4 1 Departments of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland, USA 2 Department of Dermatology, University of Maryland School of Medicine, Baltimore, Maryland, USA 3 Department of Reproductive Biology, University of Maryland School of Medicine, Baltimore, Maryland, USA 4 Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland, USA 5 Department of Surgery and Division of General and Surgical Oncology, University of Maryland School of Medicine, Baltimore, Maryland, USA 6 Department of Chemistry, University of Ottawa, Ottawa, ON, CA 7 Department of Surgery, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA Correspondence to: Richard L. Eckert, email: reckert@umaryland.edu Keywords: mesothelioma; transglutaminase; TGM2; cancer stem cell; EMT Received: April 23, 2018      Accepted: September 08, 2018      Published: October 02, 2018 ABSTRACT Mesothelioma is a rare cancer of the mesothelial cell layer of the pleura, peritoneum, pericardium and tunica vaginalis. It is typically caused by asbestos, notoriously resistant to chemotherapy and generally considered incurable with a poor life expectancy. Transglutaminase 2 (TG2), a GTP binding regulatory protein, is an important cancer stem cell survival and therapy resistance factor. We show that TG2 is highly expressed in human mesothelioma tumors and in mesothelioma cancer stem cells (MCS cells). TG2 knockdown or TG2 inhibitor treatment reduces MCS cell spheroid formation, matrigel invasion, migration and tumor formation. Time to tumor first appearance is doubled in TG2 knockout cells as compared to wild-type. In addition, TG2 loss is associated with reduced expression of stemness, and epithelial mesenchymal transition markers, and enhanced apoptosis. These studies indicate that TG2 is an important MCS cell survival protein and suggest that TG2 may serve as a mesothelioma cancer stem cell therapy target.