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

Research output: Contribution to journalArticle

Abstract

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.

LanguageEnglish
Article numbere2592
Number of pages7
JournalCell Death and Disease
Volume8
Issue number2
DOIs
Publication statusPublished - 2 Feb 2017

Fingerprint

Cell Hypoxia
Survival
Cell Survival
Epithelioid Cells
Malignant Mesothelioma
transglutaminase 2
Asbestos
Environmental Exposure
Occupational Exposure
Epithelium

Bibliographical note

Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Cite this

Zonca, Sara ; Pinton, Giulia ; Wang, Zhuo ; Soluri, Maria Felicia ; Tavian, Daniela ; Griffin, Martin ; Sblattero, Daniele ; Moro, Laura. / Tissue transglutaminase (TG2) enables survival of human malignant pleural mesothelioma cells in hypoxia. In: Cell Death and Disease. 2017 ; Vol. 8, No. 2.
@article{b14420aee8b143c693833229785b812f,
title = "Tissue transglutaminase (TG2) enables survival of human malignant pleural mesothelioma cells in hypoxia",
abstract = "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.",
author = "Sara Zonca and Giulia Pinton and Zhuo Wang and Soluri, {Maria Felicia} and Daniela Tavian and Martin Griffin and Daniele Sblattero and Laura Moro",
note = "Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.",
year = "2017",
month = "2",
day = "2",
doi = "10.1038/cddis.2017.30",
language = "English",
volume = "8",
journal = "Cell Death and Disease",
issn = "2041-4889",
publisher = "Nature Publishing Group",
number = "2",

}

Tissue transglutaminase (TG2) enables survival of human malignant pleural mesothelioma cells in hypoxia. / Zonca, Sara; Pinton, Giulia; Wang, Zhuo; Soluri, Maria Felicia; Tavian, Daniela; Griffin, Martin; Sblattero, Daniele; Moro, Laura.

In: Cell Death and Disease, Vol. 8, No. 2, e2592, 02.02.2017.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Tissue transglutaminase (TG2) enables survival of human malignant pleural mesothelioma cells in hypoxia

AU - Zonca, Sara

AU - Pinton, Giulia

AU - Wang, Zhuo

AU - Soluri, Maria Felicia

AU - Tavian, Daniela

AU - Griffin, Martin

AU - Sblattero, Daniele

AU - Moro, Laura

N1 - Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

PY - 2017/2/2

Y1 - 2017/2/2

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85011585260&partnerID=8YFLogxK

UR - http://www.nature.com/cddis/journal/v8/n2/full/cddis201730a.html

U2 - 10.1038/cddis.2017.30

DO - 10.1038/cddis.2017.30

M3 - Article

VL - 8

JO - Cell Death and Disease

T2 - Cell Death and Disease

JF - Cell Death and Disease

SN - 2041-4889

IS - 2

M1 - e2592

ER -