Combining PARP-1 inhibition and radiation in ewing sarcoma results in lethal DNA damage Journal Article
| Authors: | Lee, H. J.; Yoon, C.; Schmidt, B.; Park, D. J.; Zhang, A. Y.; Erkizan, H. V.; Toretsky, J. A.; Kirsch, D. G.; Yoon, S. S. |
| Article Title: | Combining PARP-1 inhibition and radiation in ewing sarcoma results in lethal DNA damage |
| Abstract: | Ewing sarcomas (ES) harbor a chromosomal translocation that fuses the EWS gene to an ETS transcription factor, most commonly Friend leukemia integration 1 (FLI1). The EWS-FLI1 fusion protein acts in a positive feedback loop to maintain the expression of PARP-1, which is involved in repair of DNA damage. Here, we examine the effects of PARP-1 inhibition and radiation therapy on Ewing sarcomas. In proliferation assays, the Ewing sarcoma cell lines RD-ES and SK-N-MC were much more sensitive than non-Ewing sarcoma cell lines to the PARP-1 inhibitor olaparib (Ola; IC50 0.5-1 mmol/L vs. >5 mmol/L) and to radiation (IC50 2-4Gyvs. >6 Gy). PARP-1 inhibition with short hairpinRNA(shRNA) or Ola sensitized Ewing sarcoma cells, but not non-Ewing sarcoma cells, to radiation therapy in both proliferation and colony formation assays. Using the Comet assay, radiation of Ewing sarcoma cells with Ola, compared to without Ola, resulted in more DNA damage at 1 hour (mean tail moment 36-54 vs. 26-28) and sustainedDNAdamage at 24 hours (24-29 vs. 6-8). ThisDNAdamage led to a 2.9- to 4.0-fold increase in apoptosis and a 1.6- to 2.4-fold increase in cell death. The effect of PARP-1 inhibition and radiation therapy on Ewing sarcoma cells was lost when EWS-FLI1 was silenced by shRNA. A small dose of radiation therapy (4 Gy), when combined with PARP-1 inhibition, stopped the growth of SK-NMC flank tumors xenografts. In conclusion, PARP-1 inhibition in Ewing sarcomas amplifies the level and duration of DNA damage caused by radiation therapy, leading to synergistic increases in apoptosis and cell death in a EWS-FLI1-dependent manner. Mol Cancer Ther; 12(11); 2591-600. © 2013 AACR. |
| Journal Title: | Molecular Cancer Therapeutics |
| Volume: | 12 |
| Issue: | 11 |
| ISSN: | 1535-7163 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2013-11-01 |
| Start Page: | 2591 |
| End Page: | 2600 |
| Language: | English |
| DOI: | 10.1158/1535-7163 |
| PROVIDER: | scopus |
| PMCID: | PMC3823674 |
| PUBMED: | 23966622 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 2 December 2013" - "CODEN: MCTOC" - "Source: Scopus" |
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