Extracellular signal regulated kinase 5 and inflammasome in progression of mesothelioma.

Autor:	Thompson JK; Department of Pathology and Laboratory Medicine, Larner College of Medicine, University of Vermont, Burlington, VT 05405, USA., Shukla A; Department of Pathology and Laboratory Medicine, Larner College of Medicine, University of Vermont, Burlington, VT 05405, USA., Leggett AL; Department of Pathology and Laboratory Medicine, Larner College of Medicine, University of Vermont, Burlington, VT 05405, USA., Munson PB; Department of Pathology and Laboratory Medicine, Larner College of Medicine, University of Vermont, Burlington, VT 05405, USA., Miller JM; Department of Pathology and Laboratory Medicine, Larner College of Medicine, University of Vermont, Burlington, VT 05405, USA., MacPherson MB; Department of Pathology and Laboratory Medicine, Larner College of Medicine, University of Vermont, Burlington, VT 05405, USA., Beuschel SL; Department of Pathology and Laboratory Medicine, Larner College of Medicine, University of Vermont, Burlington, VT 05405, USA., Pass HI; Department of Cardiothoracic Surgery, Langone Medical Center, New York University, New York, NY 10012, USA., Shukla A; Department of Pathology and Laboratory Medicine, Larner College of Medicine, University of Vermont, Burlington, VT 05405, USA.
Jazyk:	angličtina
Zdroj:	Oncotarget [Oncotarget] 2017 Dec 06; Vol. 9 (1), pp. 293-305. Date of Electronic Publication: 2017 Dec 06 (Print Publication: 2018).
DOI:	10.18632/oncotarget.22968
Abstrakt:	Malignant mesothelioma is an aggressive cancer in desperate need of treatment. We have previously shown that extracellular signaling regulated kinase 5 (ERK5) plays an important role in mesothelioma pathogenesis using ERK5 silenced human mesothelioma cells exhibiting significantly reduced tumor growth in immunocompromised mice. Here, we used a specific ERK 5 inhibitor, XMD8-92 in various in vitro and in vivo models to demonstrate that inhibition of ERK5 can slow down mesothelioma tumorigenesis. First, we show a dose dependent toxicity of XMD8-92 to 2 human mesothelioma cell lines growing as a monolayer. We also demonstrate the inhibition of ERK5 phosphorylation in various human mesothelioma cell lines by XMD8-92. We further confirmed the toxicity of XMD8-92 towards mesothelioma cell lines grown as spheroids in a 3-D model as well as in intraperitoneal (immune-competent) and intrapleural (immune-deficient) mouse models with and without chemotherapeutic drugs. To ascertain the mechanism, we explored the role of the nod-like receptor family member containing a pyrin domain 3 (NLRP3) inflammasome in the process. We found XMD8-92 attenuated naïve and chemotherapeutic-induced inflammasome priming and activation in mesothelioma cells. It can thus be concluded that ERK5 inhibition attenuates mesothelioma tumor growth and this phenomenon in part is regulated by the inflammasome. Competing Interests: CONFLICTS OF INTEREST The authors of this manuscript have no conflicts of interest which they wish to disclose.
Databáze:	MEDLINE
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