Ewing sarcoma inhibition by disruption of EWSR1-FLI1 transcriptional activity and reactivation of p53

被引:40
作者
van der Ent, Wietske [1 ,2 ]
Jochemsen, Aart G. [3 ]
Teunisse, Amina F. A. S. [3 ]
Krens, S. F. Gabriel [1 ]
Szuhai, Karoly [3 ]
Spaink, Herman P. [1 ]
Hogendoorn, Pancras C. W. [2 ]
Snaar-Jagalska, B. Ewa [1 ]
机构
[1] Leiden Univ, Inst Biol, NL-2300 RA Leiden, Netherlands
[2] Leiden Univ, Med Ctr, Dept Pathol, NL-2300 RA Leiden, Netherlands
[3] Leiden Univ, Med Ctr, Dept Mol Cell Biol, NL-2300 RA Leiden, Netherlands
关键词
Ewing sarcoma; drug synergism; p53; tumour growth; zebrafish; anti-cancer drug screen; molecular targeted therapy; TRANSGENIC ZEBRAFISH MODEL; DRUG DISCOVERY; CYTOGENETIC CHARACTERIZATION; CANCER MODEL; CELL-LINES; TUMORS; EXPRESSION; SYSTEM; GENE; MDM2;
D O I
10.1002/path.4378
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Translocations involving ETS-transcription factors, most commonly leading to the EWSR1-FLI1 fusion protein, are the hallmark of Ewing sarcoma. Despite knowledge of this driving molecular event, an effective therapeutic strategy is lacking. To test potential treatment regimes, we established a novel Ewing sarcoma zebrafish engraftment model allowing time-effective, dynamic quantification of Ewing sarcoma progression and tumour burden in vivo, applicable for screening of single and combined compounds. In Ewing sarcoma the tumour-suppressor gene TP53 is commonly found to be wild-type, thus providing an attractive target for treatment. Here, we study TP53 wild-type (EW7, CADO-ES1 and TC32) and TP53-deleted (SK-N-MC) Ewing sarcoma cell lines to investigate the potentiating effect of p53 reactivation by Nutlin-3 on treatment with YK-4-279 to block transcriptional activity of EWSR1-FLI1 protein. Blocking EWSR1-FLI1 transcriptional activity reduced Ewing sarcoma tumour cell burden irrespective of TP53 status. We show that simultaneous YK-4-279 treatment with Nutlin-3 to stabilize p53 resulted in an additive inhibition of TP53 wild-type Ewing sarcoma cell burden, whilst not affecting TP53-deleted Ewing sarcoma cells. Improved inhibition of proliferation and migration by combinatorial treatment was confirmed in vivo by zebrafish engraftments. Mechanistically, both compounds together additively induced apoptosis of tumour cells in vivo by engaging distinct pathways. We propose reactivation of the p53 pathway in combination with complementary targeted therapy by EWSR1-FLI1 transcriptional activity disruption as a valuable strategy against p53 wild-type Ewing sarcoma. Copyright (C) 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
引用
收藏
页码:415 / 424
页数:10
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