Tissue transglutaminase (TG2) enables survival of human malignant pleural mesothelioma cells in hypoxia.
Malignant pleural mesothelioma (MPM) is an aggressive tumor linked to environmental/occupational exposure to asbestos, characterized by the presence of significant areas of hypoxia. In this study, we firstly explored the expression and the role of transglutaminase 2 (TG2) in MPM cell adaptation to hypoxia. We demonstrated that cells derived from biphasic MPM express the full-length TG2 variant at higher levels than cells derived from epithelioid MPM and normal mesothelium. We observed a significant induction of TG2 expression and activity when cells from biphasic MPM were grown as a monolayer in chronic hypoxia or packed in spheroids, where the presence of a hypoxic core was demonstrated. We described that the hypoxic induction of TG2 was HIF-2 dependent. Importantly, TGM2-v1 silencing caused a marked and significant reduction of MPM cell viability in hypoxic conditions when compared with normoxia. Notably, a TG2-selective irreversible inhibitor that reacts with the intracellular active form of TG2, but not a non-cell-permeable inhibitor, significantly compromised cell viability in MPM spheroids. Understanding the expression and function of TG2 in the adaptation to the hypoxic environment may provide useful information for novel promising therapeutic options for MPM treatment.
Department of Pharmaceutical Sciences, University of Piemonte Orientale, Novara, Italy.
Sara
S
Zonca
Department of Pharmaceutical Sciences, University of Piemonte Orientale, Novara, Italy.
Giulia
G
Pinton
School of Life and Health Sciences, Aston University, Birmingham, UK.
Zhuo
Z
Wang
Department of Health Sciences, University of Piemonte Orientale, Novara, Italy.
Maria Felicia
MF
Soluri
Laboratory of Cellular Biochemistry and Molecular Biology, CRIBENS, Catholic University of the Sacred Heart, Milan, Italy.
Daniela
D
Tavian
School of Life and Health Sciences, Aston University, Birmingham, UK.
Martin
M
Griffin
Department of Life Sciences, University of Trieste, Trieste, Italy.
Daniele
D
Sblattero
Department of Pharmaceutical Sciences, University of Piemonte Orientale, Novara, Italy.
Laura
L
Moro
D000220:Adaptation, Biological / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D002470:Cell Survival / Q000235:genetics*; D019204:GTP-Binding Proteins / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing / Q000502:physiology; D006801:Humans; D000860:Hypoxia / Q000235:genetics* / Q000473:pathology; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008654:Mesothelioma / Q000235:genetics* / Q000473:pathology; D000086002:Mesothelioma, Malignant; D010997:Pleural Neoplasms / Q000235:genetics* / Q000473:pathology; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases / Q000235:genetics*
D014408:Biomarkers, Tumor; C000717608:TGM2 protein, human; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins