Extracellular signal regulated kinase 5 and inflammasome in progression of mesothelioma

Our plain-English summary of Extracellular signal regulated kinase 5 and inflammasome in progression of mesothelioma, by J.K. Thompson, A. Shukla, A.L. Leggett, et al (Oncotarget, 2018).

The study

• Authors: J.K. Thompson, A. Shukla, A.L. Leggett, P.B. Munson, J.M. Miller, M.B. MacPherson, S.L. Beuschel, H.I. Pass, A. Shukla
• Journal: Oncotarget
• Published: 2018;9(1):293-305
• Cited by: 15 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This laboratory study tested XMD8-92, a drug that blocks a signaling protein called ERK5, in mesothelioma models. In tumor sections from 15 patients with pleural mesothelioma, staining for activated ERK5 was more extensive than in normal lung tissue, and no correlation with tumor type was observed. XMD8-92 was toxic to two human mesothelioma cell lines, Hmeso more readily than H2373. It reduced colony formation and was toxic to cells grown as 3-D spheroids. Combined with the chemotherapy drug doxorubicin it gave a greater effect in H2373 cells, but in Hmeso cells it drastically reduced doxorubicin's effect. No added effect was seen with cisplatin. In immune-competent mice with peritoneal tumors (5 per group), daily injections significantly reduced tumor weight and volume. The effect on tumors in the chest (pleural) cavity of immune-deficient mice was less marked. The drug lowered several inflammasome-related genes and significantly reduced IL-1 beta release caused by crocidolite asbestos in human mesothelial cells. The authors concluded that the mechanism may involve the inflammasome. They noted a report suggesting ERK5 inhibitor effects could be off-target.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study: human tumor tissue staining, experiments on human and mouse mesothelioma cell lines (flat cultures, soft agar, 3-D spheroids), and mouse tumor models
• Who was studied: Tumor sections from 15 pleural mesothelioma patients (9 epithelioid, 3 biphasic, 3 sarcomatoid) plus a normal lung section. Human mesothelioma cell lines (Hmeso, H2373, HP-1, H2461, H2595) and human peritoneal mesothelial cells (LP9). Male C57/BL6 mice given mouse mesothelioma cells in the peritoneal cavity (5 per group). Nude-SCID mice given Hmeso cells in the pleural cavity (8 to 15 per group). Work was done at the University of Vermont.
• Exposure: The ERK5 inhibitor XMD8-92, alone or with doxorubicin or cisplatin. In mice it was given at 50 mg/kg into the peritoneal cavity once daily for 3 weeks. In one experiment, human mesothelial cells were exposed to the NIEHS reference sample of crocidolite asbestos (5 μg/cm2).
• Main results:
  • Pleural mesothelioma tumor sections showed more extensive staining for activated ERK5 (pERK5) than normal lung tissue on the same array.
  • No correlation of pERK5 staining with the histological type of tumor was observed in the 15 sections.
  • XMD8-92 was toxic to mesothelioma cells. Hmeso cells were more sensitive. In H2373 cells, significant effects appeared only at higher concentrations and later time points.
  • Of 4 cell lines tested, 3 showed a trend toward lower pERK5 levels after high doses of XMD8-92.
  • H2373 cells pretreated with XMD8-92 formed very few and small colonies on soft agar.
  • In the 3-D spheroid model, doxorubicin plus XMD8-92 gave a greater decrease in growth of H2373 cells. No such additive effect occurred with cisplatin.
  • In Hmeso cells, doxorubicin worked much less well when combined with XMD8-92, which the authors could not explain.
  • In the peritoneal model in immune-competent mice, tumor weight and volume were significantly reduced in XMD8-92 treated mice compared with vehicle controls.
  • In the same peritoneal model, neutrophil numbers in peritoneal lavage fluid were significantly lower in the XMD8-92 group. The reduction in total cell numbers was not significant.
  • In the pleural model in immune-deficient mice, the effect on tumors was less marked than in the peritoneal model.
  • In H2373 and Hmeso cells, XMD8-92 lowered mRNA levels of several inflammasome-related genes.
  • NLRP3 levels went down in H2373 cells at 24 and 48 hours but went up in Hmeso cells.
  • XMD8-92 blocked doxorubicin-induced inflammasome activation in H2373 cells but did not reduce cisplatin-induced activation.
  • XMD8-92 pretreatment significantly reduced IL-1 beta release caused by asbestos in LP9 human mesothelial cells.
  • In mice, cisplatin combined with XMD8-92 showed no combined effect on tumor growth.
• The authors' conclusion: The authors concluded that XMD8-92 can reduce mesothelioma tumor growth in pleural and peritoneal mouse models, and that the mechanism may involve inflammasome inactivation.
• Limitations the authors state:
  • No benign pleural lesions were available for comparison, so normal lung was used instead.
  • The authors noted another report suggesting that the effects of ERK5 inhibitors could be off-target, and said more specific inhibitors should be tried.
  • More experiments with other drugs, such as pemetrexed, are needed to settle the question of combined drug treatment.
  • How ERK5 regulates the inflammasome remains to be studied.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Malignant Mesothelioma, Tumorigenesis.

Related studies

• Extracellular signal-regulated kinase 5: a potential therapeutic target for malignant mesotheliomas — A. Shukla, J.M. Miller, et al. (2013)
• Extracellular signal-regulated kinase 5 and cyclic AMP response element binding protein are novel pathways inhibited by vandetanib (ZD6474) and doxorubicin in mesotheliomas — M. Sayan, A. Shukla, et al. (2014)
• An extracellular signal-regulated kinase 2 survival pathway mediates resistance of human mesothelioma cells to asbestos-induced injury — A. Shukla, T.F. Barrett, et al. (2011)
• Asbestos-mediated CREB phosphorylation is regulated by protein kinase A and extracellular signal-regulated kinases 1/2 — C.A. Barlow, T.F. Barrett, et al. (2007)
• Role of extracellular signal-regulated protein kinases in apoptosis by asbestos and H2O2 — L.A. Jiménez, C. Zanella, et al. (1997)
• Different accumulation of activated extracellular signal-regulated kinases (ERK 1/2) and role in cell-cycle alterations by epidermal growth factor, hydrogen peroxide, or asbestos in pulmonary epithelial cells — S. Buder-Hoffmann, C. Palmer, et al. (2001)

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