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.
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, shERK5malignant 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 shERK5malignant mesothelioma cell lines into SCIDmice 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: M A Dickson; W C Hahn; Y Ino; V Ronfard; J Y Wu; R A Weinberg; D N Louis; F P Li; J G Rheinwald Journal: Mol Cell Biol Date: 2000-02 Impact factor: 4.272
Authors: Christopher P Regan; Wei Li; Diane M Boucher; Stephen Spatz; Michael S Su; Keisuke Kuida Journal: Proc Natl Acad Sci U S A Date: 2002-07-01 Impact factor: 11.205
Authors: Van T Hoang; Thomas J Yan; Jane E Cavanaugh; Patrick T Flaherty; Barbara S Beckman; Matthew E Burow Journal: Cancer Lett Date: 2017-01-30 Impact factor: 8.679
Authors: Catherine M Westbom; Anurag Shukla; Maximilian B MacPherson; Elizabeth C Yasewicz; Jill M Miller; Stacie L Beuschel; Chad Steele; Harvey I Pass; Pamela M Vacek; Arti Shukla Journal: Am J Pathol Date: 2014-08-08 Impact factor: 4.307
Authors: Katherine G Finegan; Diana Perez-Madrigal; James R Hitchin; Clare C Davies; Allan M Jordan; Cathy Tournier Journal: Cancer Res Date: 2015-02-03 Impact factor: 12.701
Authors: M J Lathrop; E K Sage; S L Macura; E M Brooks; F Cruz; N R Bonenfant; D Sokocevic; M B MacPherson; S L Beuschel; C W Dunaway; A Shukla; S M Janes; C Steele; B T Mossman; D J Weiss Journal: Cancer Gene Ther Date: 2014-12-19 Impact factor: 5.987
Authors: Mutlay Sayan; Arti Shukla; Maximilian B MacPherson; Sherrill L Macura; Jedd M Hillegass; Timothy N Perkins; Joyce K Thompson; Stacie L Beuschel; Jill M Miller; Brooke T Mossman Journal: Am J Respir Cell Mol Biol Date: 2014-11 Impact factor: 6.914