Oncotarget

Research Papers:

Extracellular signal regulated kinase 5 and inflammasome in progression of mesothelioma

Joyce K. Thompson, Anurag Shukla, Alan L. Leggett, Phillip B. Munson, Jill M. Miller, Maximilian B. MacPherson, Stacie L. Beuschel, Harvey I. Pass and Arti Shukla _

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Oncotarget. 2018; 9:293-305. https://doi.org/10.18632/oncotarget.22968

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Abstract

Joyce K. Thompson1, Anurag Shukla1, Alan L. Leggett1, Phillip B. Munson1, Jill M. Miller1, Maximilian B. MacPherson1, Stacie L. Beuschel1, Harvey I. Pass2 and Arti Shukla1

1Department of Pathology and Laboratory Medicine, Larner College of Medicine, University of Vermont, Burlington, VT 05405, USA

2Department of Cardiothoracic Surgery, Langone Medical Center, New York University, New York, NY 10012, USA

Correspondence to:

Arti Shukla, email: [email protected]

Keywords: mesothelioma; extracellular signal regulated kinase 5; inflammasome; asbestos; XMD8-92

Received: September 13, 2017     Accepted: November 10, 2017     Published: December 06, 2017

ABSTRACT

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.


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