SS18-SSX2 and the mitochondrial apoptosis pathway in mouse and human synovial sarcomas.
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 a mouse model. Elevated expression of BCL2 is considered a consistent feature of the synovial sarcoma expression profile. Our objective was to evaluate the expression of apoptotic pathway members in synovial sarcomas and interrogate the impact of modulating SS18-SSX expression on this pathway. We show in human and murine synovial sarcoma cells that SS18-SSX increases BCL2 expression, but represses other anti-apoptotic genes, including MCL1 and BCL2A1. This repression is achieved by directly suppressing expression via binding through activating transcription factor 2 (ATF2) to the cyclic adenosine monophosphate (AMP) response element (CRE) in the promoters of these genes and recruiting TLE1/Groucho. The suppression of these two anti-apoptotic pathways silences the typical routes by which other tumors evade BH3-domain peptidomimetic pharmacotherapy. We show that mouse and human synovial sarcoma cells are sensitive in vitro to ABT-263, a BH3-peptidomimetic, much more than the other tested cancer cell lines. ABT-263 also enhances the sensitivity of these cells to doxorubicin, a traditional cytotoxic chemotherapy used for synovial sarcoma. We also demonstrate the capacity of ABT-263 to stunt synovial sarcomagenesis in vivo in a genetic mouse model. These data recommend pursuit of BH3-peptidomimetic pharmacotherapy in human synovial sarcomas.
Department of Orthopaedics, University of Utah, Salt Lake City, UT 84112-5331, USA.
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Jones
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Jin
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Lenz
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Randall
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Underhill
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Nielsen
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Sharma
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Capecchi
D051698:Activating Transcription Factor 2 / Q000235:genetics; D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics*; D004317:Doxorubicin / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D015778:Minor Histocompatibility Antigens; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D013584:Sarcoma, Synovial / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D013449:Sulfonamides / Q000494:pharmacology
C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; D000814:Aniline Compounds; D000970:Antineoplastic Agents; C096816:BCL2-related protein A1; C579094:Mcl1 protein, mouse; D015778:Minor Histocompatibility Antigens; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D015514:Oncogene Proteins, Fusion; D019253:Proto-Oncogene Proteins c-bcl-2; C116512:SYT-SSX fusion protein; D013449:Sulfonamides; D004317:Doxorubicin; C528561:navitoclax