Publication date: May 07, 2019
Overexpression and activation of c-Jun-N-terminal kinases (JNK) 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, function in melanoma. Our previous study has 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 on melanoma cell proliferation and invasiveness, we expressed 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 high 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.
Du, L., Anderson, A., Nguyen, K., Ojeda, S.S., , Ortiz-Rivera, Nguyen, T.N., Zhang, T., Kaoud, T.S., Gray, N.S., Dalby, K.N., and Tsai, K.Y. JNK2 is required for tumorigenic properties of melanoma cells. 22531. 2019 ACS Chem Biol.
- BRAF as a Driver in Melanoma
- K27-linked ubiquitination of BRAF by ITCH engages cytokine response to maintain MEK-ERK signaling.
- Transcriptional regulation of autophagy-lysosomal function in BRAF-driven melanoma progression and chemoresistance.
- Transcriptional regulation of autophagy-lysosomal function in BRAF-driven melanoma progression and chemoresistance
- Blocking BRAF ubiquitination may be an effective treatment approach in melanoma