SS18-SSX2 and the mitochondrial apoptosis pathway in mouse and human synovial sarcomas

摘要: Synovial sarcoma is a deadly malignancy with limited sensitivity to traditional cytotoxic chemotherapy. SS18-SSX fusion oncogene expression characterizes human synovial sarcomas and drives oncogenesis in mouse model. Elevated of BCL2 considered consistent feature the profile. Our objective was evaluate apoptotic pathway members interrogate impact modulating on this pathway. We show murine cells that increases expression, but represses other anti-apoptotic genes, including MCL1 BCL2A1. This repression achieved by directly suppressing via binding through activating transcription factor 2 (ATF2) cyclic adenosine monophosphate (AMP) response element (CRE) promoters these genes recruiting TLE1/Groucho. The suppression two pathways silences typical routes which tumors evade BH3-domain peptidomimetic pharmacotherapy. are sensitive vitro ABT-263, BH3-peptidomimetic, much more than tested cancer cell lines. ABT-263 also enhances doxorubicin, chemotherapy used for sarcoma. demonstrate capacity stunt sarcomagenesis vivo genetic These data recommend pursuit BH3-peptidomimetic pharmacotherapy sarcomas.