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

K. B. Jones, L. Su, H. Jin, C. Lenz, R Randall, T. M. Underhill, T. O. Nielsen, S. Sharma, M. R. Capecchi

Research output: Contribution to journalArticle

24 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2365-2371
Number of pages7
JournalOncogene
Volume32
Issue number18
DOIs
StatePublished - May 2 2013
Externally publishedYes

Keywords

  • apoptosis
  • chemotherapy
  • mouse model
  • synovial sarcoma
  • targeted therapy

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Jones, K. B., Su, L., Jin, H., Lenz, C., Randall, R., Underhill, T. M., Nielsen, T. O., Sharma, S., & Capecchi, M. R. (2013). SS18-SSX2 and the mitochondrial apoptosis pathway in mouse and human synovial sarcomas. Oncogene, 32(18), 2365-2371. https://doi.org/10.1038/onc.2012.247