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

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.

• Authors: Arti Shukla, Jill M Miller, Christopher Cason, Mutlay Sayan, Maximilian B MacPherson, Stacie L Beuschel, Jedd Hillegass, Pamela M Vacek, Harvey I Pass, Brooke T Mossman
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 19 Issue 8 Pg. 2071-83 (Apr 15 2013) ISSN: 1557-3265 [Electronic] United States
• PMID: 23446998 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Cytokines
• Asbestos, Crocidolite
• Doxorubicin
• Mitogen-Activated Protein Kinase 7
• Cisplatin

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Asbestos, Crocidolite (pharmacology)
• Blotting, Western
• Cell Line, Tumor
• Cell Survival (drug effects, genetics)
• Cisplatin (pharmacology)
• Combined Modality Therapy
• Cytokines (genetics, metabolism)
• Doxorubicin (pharmacology)
• Enzyme Activation (drug effects)
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Humans
• Mesothelioma (genetics, pathology, therapy)
• Mice
• Mice, SCID
• Mitogen-Activated Protein Kinase 7 (genetics, metabolism)
• Oligonucleotide Array Sequence Analysis
• RNA Interference
• Reverse Transcriptase Polymerase Chain Reaction
• Tumor Burden (drug effects, genetics)
• Xenograft Model Antitumor Assays