Background: BRAF-mutant melanoma is characterized by aggressive metastatic potential and therapeutic resistance. The innate immune receptor RIG-has emerged as a potential target in melanoma therapies but the contributing pathways involved in anti-cancer activity are poorly characterized. Methods: Baseline and ATRA-induced expression of RIG-in nine (wild type and 6 BRAF-mutant) melanoma cell lines was measured with Q-PCR and Western blot. Ligand-specific stimulation of RIG-was detected by Q-PCR and ELISA. Activation of the RIG-I-coupled IRF3, NF-κB and MAPK pathways was tested with protein array and Western blot. Cell proliferation and apoptosis was monitored by flow cytometry and cell counting. Down modulation of MKP-expression in melanoma cells was performed by specific siRNA. Results: Short-term ATRA pre-treatment increases the expression of RIG-in BRAF-mutant melanoma cells. Specific activation of RIG-by 5[U+02B9]ppp-dsRNA leads to increased activity of the IRF3-IFNβ pathway but does not influence NF-κB signaling. RIG-mediates the targeted dephosphorylation of several MAPKs (p38, RSK1, GSK-3α/β, HSP27) via the endogenous regulator MKP-resulting in decreased melanoma cell proliferation. Conclusion: RIG-has the potential to exert anticancer activity in BRAF-mutant melanoma via controlling IFNβ production and MAPK signaling. This is the first study showing that RIG-activation results in MKP-1-mediated inhibition of cell proliferation via controlling the p38-HSP27, c-Jun and rpS6 pathways thus identifying RIG-and MKP-as novel and promising therapeutical targets.
ASJC Scopus subject areas
- Cell Biology