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Dominant negative PDGF-C inhibits growth of Ewing family tumor cell lines

Oncogene volume 21, pages 3847–3854 (2002)Cite this article

Abstract

Nearly all cases of Ewing Family Tumors (EFT) harbor chimeric EWS/ETS transcription factors which are thought to aberrantly regulate transcriptional targets of phenotypic consequence. We have recently demonstrated that EWS/ETS proteins up-regulate platelet derived growth factor-C (PDGF-C), a novel transforming growth factor. To determine if PDGF-C signaling contributes to the malignant phenotype of EFT cell lines, we attempted to disrupt this presumed autocrine loop. AG1296, a PDGF receptor selective tyrosine kinase inhibitor, markedly inhibits anchorage-independent growth in an EFT cell line. To effect specific disruption, we have developed a dominant negative form of PDGF-C which is appropriately secreted and processed. This mutant has greatly reduced activity as a PDGF receptor agonist. When co-expressed with PDGF-C in a fibroblast transformation model, this dominant negative dramatically inhibits anchorage-independent growth. When this mutant is expressed in EFT cell lines, there is a similar reduction in anchorage-independent growth. This demonstrates that specific inhibition of PDGF-C signaling in EFT cell lines partially reverts their phenotype. These data support a significant role of PDGF-C in the biology of EFT. They also suggest that PDGF-C driven signaling may be a possible therapeutic target of more clinically relevant tyrosine kinase inhibitors.

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Acknowledgements

WA May is supported with funding from the American Cancer Society (RPG-99-096-01) and the National Cancer Institute (CA90666). The authors wish to acknowledge Dr Randy Wada for critical review of the manuscript.

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  1. Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA

    Jeffrey P Zwerner & William A May

  2. Department of Pediatrics and Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama, USA

    William A May

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  1. Jeffrey P Zwerner
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  2. William A May
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Correspondence to William A May.

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Zwerner, J., May, W. Dominant negative PDGF-C inhibits growth of Ewing family tumor cell lines. Oncogene 21, 3847–3854 (2002). https://doi.org/10.1038/sj.onc.1205486

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