Tissue transglutaminase (TG2) enables survival of human malignant pleural mesothelioma cells in hypoxia.

Sara Zonca, Giulia Pinton, Zhuo Wang, Maria Felicia Soluri, Daniela Tavian, Martin Griffin, Daniele Sblattero, Laura Moro

Cell death & disease 2017 Feb 02

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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.

Citation

Sara Zonca, Giulia Pinton, Zhuo Wang, Maria Felicia Soluri, Daniela Tavian, Martin Griffin, Daniele Sblattero, Laura Moro. Tissue transglutaminase (TG2) enables survival of human malignant pleural mesothelioma cells in hypoxia. Cell death & disease. 2017 Feb 02;8(2):e2592