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.
Highlights
Malignant mesothelioma is an aggressive cancer of mesothelial cell linings of pleural, peritoneal or pericardial cavities and rarely of tunica vaginalis [1]
Based on in vivo and in vitro studies using genetically modified mesothelioma cell lines, our group was first to demonstrate that extracellular signaling regulated kinase 5 (ERK5) plays a significant role in mesothelioma tumorigenesis and projected it as a potential therapeutic target [4]
With the development of a specific ERK5 inhibitor, XMD8-92 [8], it became possible to test this small molecule inhibitor in pre-clinical mesothelioma models, so that a potential therapy can be developed for this deadly cancer
Summary
Malignant mesothelioma is an aggressive cancer of mesothelial cell linings of pleural, peritoneal or pericardial cavities and rarely of tunica vaginalis [1]. It is a locally invasive cancer with limited treatment strategies and there is a dire need to identify new therapeutic options in order to improve patients’ prognosis. We demonstrated the effect of an ERK5 specific inhibitor in various in vitro and in vivo models including immune-competent mice and showed the role of the inflammasome in the process. A recent review summarizes the tumorigenic www.impactjournals.com/oncotarget properties of ERK5 in both in vitro and in vivo models, which highlights various approaches used to demonstrate the role of ERK5 in different types of cancers [6]. Our previous results were generated by genetic manipulations of ERK5 in immune-deficient mice and in the present study we moved our research to the step by using a specific small molecule inhibitor of ERK5 on mesothelioma tumor growth in immune competent mice
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