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ACS Chem Biol. 2019 Jul 19;14(7):1426-1435. doi: 10.1021/acschembio.9b00083. Epub 2019 May 17.

JNK2 Is Required for the Tumorigenic Properties of Melanoma Cells.

Author information

1
Department of Translational Molecular Pathology , The University of Texas M. D. Anderson Cancer Center , Houston , Texas 77030 , United States.
2
Departments of Anatomic Pathology and Tumor Biology, Co-Director, Donald A. Adam Melanoma & Skin Cancer Center of Excellence , Moffitt Cancer Center , Tampa , Florida 33612 , United States.
3
Department of Cancer Biology , Dana-Farber Cancer Institute , Boston , Massachusetts 02215 , United States.
4
Department of Biological Chemistry and Molecular Pharmacology , Harvard Medical School , Boston , Massachusetts 02115 , United States.
5
Division of Chemical Biology and Medicinal Chemistry, College of Pharmacy , The University of Texas at Austin , Austin , Texas 78712 , United States.
6
Department of Medicinal Chemistry, Faculty of Pharmacy , Minia University , 61519 Minia , Egypt.

Abstract

Overexpression and activation of c-Jun N-terminal kinases (JNKs) have been observed in multiple cancer cell lines and tumor samples. Various JNK isoforms have been reported to promote lung and liver cancer, as well as keratinocyte transformation, suggesting an important role of JNK signaling in promoting tumor development. However, there are three JNK isoforms, and it is unclear how each individual isoform, especially the ubiquitously expressed JNK1 and JNK2, functions in melanoma. Our previous study found that C116S mutations in both JNK1 and JNK2 rendered them insensitive to the covalent pan-JNK inhibitor JNK-IN-8 while retaining kinase activity. To delineate the specific roles of JNK1 and JNK2 in melanoma cell proliferation and invasiveness, we expressed the wild type (WT) and C116S mutants in melanoma cell lines and used JNK-IN-8 to enable chemical-genetic dissection of JNK1 and JNK2 activity. We found that the JNK2C116S allele consistently enhanced colony proliferation and cell invasiveness in the presence of JNK-IN-8. When cells individually expressing WT or C116S JNK1/2 were subcutaneously implanted into immunodeficient mice, we again found that bypass of JNK-IN-8-mediated inhibition of JNK signaling by expression of JNK2C116S specifically resulted in enhanced tumor growth in vivo. In addition, we observed a high level of JNK pathway activation in some human BRAF inhibitor (BRAFi) resistant melanoma cell lines relative to their BRAFi sensitive isogenic counterparts. JNK-IN-8 significantly enhanced the response to dabrafenib in resistant cells overexpressing JNK1WT, JNK2WT, and JNK1C116S but had no effect on cells expressing JNK2C116S, suggesting that JNK2 signaling is also crucial for BRAFi resistance in a subset of melanomas. Collectively, our data show that JNK2 activity is specifically required for melanoma cell proliferation, invasiveness, and BRAFi resistance and that this activity is most important in the context of JNK1 suppression, thus providing a compelling rationale for the development of JNK2 selective inhibitors as a potential therapy for the treatment of melanoma.

PMID:
31063355
DOI:
10.1021/acschembio.9b00083

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