Extracellular Signal-regulated Kinase 5: a Potential Therapeutic Target for Malignant Mesotheliomas

Overview

Journal Clin Cancer Res

Specialty Oncology

Date 2013 Mar 1

PMID 23446998

Citations 24

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

Affiliations

Soon will be listed here.

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.

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References

Saxena A, Chua T . Results of systemic pemetrexed-based combination chemotherapy versus cytoreductive surgery and hyperthermic intraperitoneal cisplatin and doxorubicin on survival in malignant peritoneal mesothelioma. Lung Cancer. 2009; 66(2):269-70. DOI: 10.1016/j.lungcan.2009.08.007. View

Hillegass J, Shukla A, Lathrop S, MacPherson M, Beuschel S, Butnor K . Inflammation precedes the development of human malignant mesotheliomas in a SCID mouse xenograft model. Ann N Y Acad Sci. 2010; 1203:7-14. PMC: 2936775. DOI: 10.1111/j.1749-6632.2010.05554.x. View

Klominek J, Baskin B, Liu Z, Hauzenberger D . Hepatocyte growth factor/scatter factor stimulates chemotaxis and growth of malignant mesothelioma cells through c-met receptor. Int J Cancer. 1998; 76(2):240-9. DOI: 10.1002/(sici)1097-0215(19980413)76:2<240::aid-ijc12>3.0.co;2-g. View

Suzuki E, Kim S, Cheung H, Corbley M, Zhang X, Sun L . A novel small-molecule inhibitor of transforming growth factor beta type I receptor kinase (SM16) inhibits murine mesothelioma tumor growth in vivo and prevents tumor recurrence after surgical resection. Cancer Res. 2007; 67(5):2351-9. DOI: 10.1158/0008-5472.CAN-06-2389. View

Mossman B, Kamp D, Weitzman S . Mechanisms of carcinogenesis and clinical features of asbestos-associated cancers. Cancer Invest. 1996; 14(5):466-80. DOI: 10.3109/07357909609018904. View

Wang X, Martindale J, Holbrook N . Requirement for ERK activation in cisplatin-induced apoptosis. J Biol Chem. 2000; 275(50):39435-43. DOI: 10.1074/jbc.M004583200. View

Reale F, Griffin T, Compton J, Graham S, Townes P, Bogden A . Characterization of a human malignant mesothelioma cell line (H-MESO-1): a biphasic solid and ascitic tumor model. Cancer Res. 1987; 47(12):3199-205. View

McCracken S, Ramsay A, Heer R, Mathers M, Jenkins B, Edwards J . Aberrant expression of extracellular signal-regulated kinase 5 in human prostate cancer. Oncogene. 2007; 27(21):2978-88. DOI: 10.1038/sj.onc.1210963. View

Kato Y, Tapping R, Huang S, WATSON M, Ulevitch R, Lee J . Bmk1/Erk5 is required for cell proliferation induced by epidermal growth factor. Nature. 1998; 395(6703):713-6. DOI: 10.1038/27234. View

10.

Xiao C, Zhang L, Cheng Q, Zhang L . The activation of extracellular signal-regulated protein kinase 5 in spinal cord and dorsal root ganglia contributes to inflammatory pain. Brain Res. 2008; 1215:76-86. DOI: 10.1016/j.brainres.2008.03.065. View

11.

Pass H, Stevens E, Oie H, Tsokos M, Abati A, Fetsch P . Characteristics of nine newly derived mesothelioma cell lines. Ann Thorac Surg. 1995; 59(4):835-44. DOI: 10.1016/0003-4975(95)00045-m. View

12.

Sticht C, Freier K, Knopfle K, Flechtenmacher C, Pungs S, Hofele C . Activation of MAP kinase signaling through ERK5 but not ERK1 expression is associated with lymph node metastases in oral squamous cell carcinoma (OSCC). Neoplasia. 2008; 10(5):462-70. PMC: 2373911. DOI: 10.1593/neo.08164. View

13.

Vandermeers F, Hubert P, Delvenne P, Mascaux C, Grigoriu B, Burny A . Valproate, in combination with pemetrexed and cisplatin, provides additional efficacy to the treatment of malignant mesothelioma. Clin Cancer Res. 2009; 15(8):2818-28. DOI: 10.1158/1078-0432.CCR-08-1579. View

14.

Linder C, Linder S, Munck-Wikland E, Strander H . Independent expression of serum vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in patients with carcinoma and sarcoma. Anticancer Res. 1998; 18(3B):2063-8. View

15.

Shukla A, Barrett T, Nakayama K, Nakayama K, Mossman B, Lounsbury K . Transcriptional up-regulation of MMP12 and MMP13 by asbestos occurs via a PKCdelta-dependent pathway in murine lung. FASEB J. 2006; 20(7):997-9. DOI: 10.1096/fj.05-4554fje. View

16.

Yan F, Wang X, Pan C . [Expression of ERK5 in multidrug-resistant hepatocellular carcinoma cell line]. Nan Fang Yi Ke Da Xue Xue Bao. 2009; 29(3):483-6. View

17.

Dickson M, Hahn W, Ino Y, Ronfard V, Wu J, Weinberg R . Human keratinocytes that express hTERT and also bypass a p16(INK4a)-enforced mechanism that limits life span become immortal yet retain normal growth and differentiation characteristics. Mol Cell Biol. 2000; 20(4):1436-47. PMC: 85304. DOI: 10.1128/MCB.20.4.1436-1447.2000. View

18.

de Melo M, Gerbase M, Curran J, Pache J . Phosphorylated extracellular signal-regulated kinases are significantly increased in malignant mesothelioma. J Histochem Cytochem. 2006; 54(8):855-61. DOI: 10.1369/jhc.5A6807.2006. View

19.

Razumovskaya E, Sun J, Ronnstrand L . Inhibition of MEK5 by BIX02188 induces apoptosis in cells expressing the oncogenic mutant FLT3-ITD. Biochem Biophys Res Commun. 2011; 412(2):307-12. DOI: 10.1016/j.bbrc.2011.07.089. View

20.

Hillegass J, Blumen S, Cheng K, MacPherson M, Alexeeva V, Lathrop S . Increased efficacy of doxorubicin delivered in multifunctional microparticles for mesothelioma therapy. Int J Cancer. 2010; 129(1):233-44. PMC: 3017728. DOI: 10.1002/ijc.25666. View