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SS18-SSX2 and the mitochondrial apoptosis pathway in mouse and human synovial sarcomas.
- Source :
-
Oncogene . 5/2/2013, Vol. 32 Issue 18, p2365-2371. 7p. - Publication Year :
- 2013
-
Abstract
- 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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 09509232
- Volume :
- 32
- Issue :
- 18
- Database :
- Academic Search Index
- Journal :
- Oncogene
- Publication Type :
- Academic Journal
- Accession number :
- 87383317
- Full Text :
- https://doi.org/10.1038/onc.2012.247