Extracellular signal-regulated kinase 5: a potential therapeutic target for malignant mesotheliomas

Our plain-English summary of Extracellular signal-regulated kinase 5: a potential therapeutic target for malignant mesotheliomas, by A. Shukla, J.M. Miller, C. Cason, et al (Clinical Cancer Research, 2013).

The study

• Authors: A. Shukla, J.M. Miller, C. Cason, M. Sayan, M.B. MacPherson, S.L. Beuschel, J. Hillegass, P.M. Vacek, H.I. Pass, B.T. Mossman
• Journal: Clinical Cancer Research
• Published: 2013;19(8):2071-83
• Cited by: 34 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Purpose: Malignant mesothelioma is a devastating disease with a need for new treatment strategies. In the present study, we showed the importance of extracellular signal-regulated kinase 5 (ERK5) in malignant mesothelioma tumor growth and treatment.

Experimental Design: ERK5 as a target for malignant mesothelioma therapy was verified using mesothelial and mesothelioma cell lines as well as by xenograft severe combined immunodeficient (SCID) mouse models.

Results: We first showed that crocidolite asbestos activated ERK5 in LP9 cells and mesothelioma cell lines exhibit constitutive activation of ERK5. Addition of doxorubicin resulted in further activation of ERK5 in malignant mesothelioma cells. ERK5 silencing increased doxorubicin-induced cell death and doxorubicin retention in malignant mesothelioma cells. In addition, shERK5 malignant mesothelioma lines exhibited both attenuated colony formation on soft agar and invasion of malignant mesothelioma cells in vitro that could be related to modulation of gene expression linked to cell proliferation, apoptosis, migration/invasion, and drug resistance as shown by microarray analysis. Most importantly, injection of shERK5 malignant mesothelioma cell lines into SCID mice showed significant reduction in tumor growth using both subcutaneous and intraperitoneal models. Assessment of selected human cytokine profiles in peritoneal lavage fluid from intraperitoneal shERK5 and control tumor-bearing mice showed that ERK5 was critical in regulation of various proinflammatory (RANTES/CCL5, MCP-1) and angiogenesis-related (interleukin-8, VEGF) cytokines. Finally, use of doxorubicin and cisplatin in combination with ERK5 inhibition showed further reduction in tumor weight and volume in the intraperitoneal model of tumor growth.

Conclusion: ERK5 inhibition in combination with chemotherapeutic drugs is a beneficial strategy for combination therapy in patients with malignant mesothelioma.

In plain English

This preclinical laboratory study examined ERK5, a cell-signaling protein, in malignant mesothelioma. The authors used human cells grown in the laboratory and human mesothelioma cells implanted in immunodeficient (SCID) mice. Crocidolite asbestos increased activated ERK5 in human peritoneal mesothelial cells (LP9), while glass beads did not. Four of 5 mesothelioma cell lines showed more activated ERK5 than LP9 cells, and the chemotherapy drug doxorubicin further activated ERK5 in 3 of 5 lines. When ERK5 was silenced, mesothelioma cells were killed more readily by doxorubicin, kept more of the drug inside, formed fewer colonies and invaded less. The authors observed no effect on migration and no statistically significant effect on proliferation. In mice, tumors from ERK5-silenced cells grew more slowly under the skin and caused less tumor burden in the abdomen. The abdominal fluid of those mice held fewer inflammatory cells and lower levels of several human cytokines. Adding doxorubicin or cisplatin reduced tumors further. The authors concluded that ERK5 inhibition combined with chemotherapy could reduce mesothelioma growth. No patients were treated, and the authors left testing of specific ERK5-blocking drugs to future studies.

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: Preclinical laboratory study: cell culture experiments plus mouse xenograft experiments (human mesothelioma cells implanted under the skin or into the abdominal cavity of SCID mice)
• Who was studied: Human peritoneal mesothelial cells (LP9/TERT-1); five human malignant mesothelioma cell lines (HMESO, H2373, H2595, H2461, HP-1); 6-week-old Fox Chase SCID mice, about 4 to 6 per group, at the University of Vermont College of Medicine
• Exposure: NIEHS reference crocidolite asbestos (glass beads as a non-fibrous control) added to LP9 cells; genetic silencing of ERK5 (shERK5) in HMESO and H2373 mesothelioma cells; the chemotherapy drugs doxorubicin (0.5 mg/kg, 3 times per week for 2 weeks in mice) and cisplatin (single 2 mg/kg dose in mice)
• Main results:
  • In LP9 human mesothelial cells, crocidolite asbestos increased activated (phosphorylated) ERK5; glass beads at the same surface area did not
  • Glass beads, the negative control, did not activate ERK5
  • 4 of 5 mesothelioma cell lines showed higher activated ERK5 than LP9 cells
  • Doxorubicin significantly activated ERK5 in 3 of 5 mesothelioma cell lines
  • ERK5-silenced mesothelioma cells were more sensitive to doxorubicin killing
  • ERK5-silenced mesothelioma cells retained more doxorubicin than control cells
  • ERK5 silencing significantly reduced colony formation in soft agar and invasion
  • The authors observed no effect of ERK5 silencing on migration in either cell line
  • The authors observed no statistically significant effect of ERK5 silencing on proliferation (data not shown)
  • Microarray analysis of HMESO cells found 812 genes up- or downregulated after ERK5 silencing
  • In the subcutaneous mouse model, ERK5 silencing significantly inhibited tumor growth for both cell lines, by tumor volume over time and by final tumor weight
  • In the intraperitoneal model, doxorubicin alone (0.5 mg/kg) did not significantly decrease tumor burden
  • In the intraperitoneal model, ERK5 silencing significantly decreased tumor burden, with a further decrease when combined with doxorubicin
  • ERK5 silencing reduced the accumulation of inflammatory cells in peritoneal lavage fluid
  • ERK5 silencing reduced the levels of the human cytokines IL-8, VEGF, MCP-1 and CCL5/RANTES in peritoneal lavage fluid
  • ERK5 silencing combined with a single cisplatin dose reduced tumor volume and weight; the authors described the effect as synergistic
• The authors' conclusion: The authors concluded that ERK5 inhibition can reduce mesothelioma tumor growth, and has a greater effect combined with chemotherapy drugs than either drug alone, making it a potential treatment strategy
• Limitations the authors state:
  • The authors could not link the level of constitutive ERK5 activation to how aggressive the mesothelioma cells were
  • The authors found no correlation between constitutive ERK5 activation and doxorubicin-induced cell death in the 5 cell lines
  • The authors noted that ERK5's effects are multifaceted and that pathway redundancy could lead to paradoxical results
  • ERK5 was blocked genetically in this study; the authors left testing of specific ERK5 inhibitor drugs to future studies

Topics

The National Library of Medicine indexes this study under subjects our site covers: Crocidolite, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Mesothelioma, Crocidolite, Doxorubicin, Apoptosis, Cytokine, Angiogenesis, Cisplatin.

Related studies

• 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)
• Extracellular signal regulated kinase 5 and inflammasome in progression of mesothelioma — J.K. Thompson, A. Shukla, et al. (2018)
• 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)
• Persistent localization of activated extracellular signal-regulated kinases (ERK1/2) is epithelial cell-specific in an inhalation model of asbestosis — A.B. Cummins, C. Palmer, et al. (2003)

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