EWS-FLI1 and RNA helicase A interaction inhibitor YK-4-279 inhibits growth of neuroblastoma
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Wenjing Sun1,5, Yesenia Rojas1, Hao Wang2,6, Yang Yu1, Yongfeng Wang3, Zhenghu Chen3, Kimal Rajapakshe4, Xin Xu3, Wei Huang3, Saurabh Agarwal3, Roma H. Patel1, Sarah Woodfield1, Yanling Zhao3, Jingling Jin1, Hong Zhang2, Angela Major7, M. John Hicks7, Jason M. Shohet3, Sanjeev A. Vasudevan1, Cristian Coarfa4, Jianhua Yang3 and Jed G. Nuchtern1
1Pediatric Surgery Division, Michael E. Debakey Department of Surgery, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX 77030, USA
2Department of Pathology, MD Anderson Cancer Center, Houston, TX 77030, USA
3Department of Pediatrics, Texas Children’s Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
4Department of Molecular and Cell Biology, Baylor College of Medicine, Houston, TX 77030, USA
5Laboratory of Medical Genetics, Harbin Medical University, Harbin, Heilongjiang 150081, China
6Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China
7Department of Pathology, Texas Children’s Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
Jed G. Nuchtern, email: firstname.lastname@example.org
Keywords: neuroblastoma; YK-4-279; chemotherapy; doxorubicin; EWSR1
Abbreviations: NB, neuroblastoma; RHA, RNA helicase A; Dox, doxorubicin
Received: July 12, 2017 Accepted: August 21, 2017 Published: October 19, 2017
Treatment failure in high risk neuroblastoma (NB) is largely due to the development of chemotherapy resistance. We analyzed the gene expression changes associated with exposure to chemotherapy in six high risk NB tumors with the aid of the Connectivity Map bioinformatics platform. Ten therapeutic agents were predicted to have a high probability of reversing the transcriptome changes associated with neoadjuvant chemotherapy treatment. Among these agents, initial screening showed the EWS-FLI1 and RNA helicase A interaction inhibitor YK-4-279, had obvious cytotoxic effects on NB cell lines. Using a panel of NB cell lines, including MYCN nonamplified (SK-N-AS, SH-SY5Y, and CHLA-255), and MYCN amplified (NB-19, NGP, and IMR-32) cell lines, we found that YK-4-279 had cytotoxic effects on all lines tested. In addition, YK-4-279 also inhibited cell proliferation and anchorage-independent growth and induced cell apoptosis of these cells. YK-4-279 enhanced the cytotoxic effect of doxorubicin (Dox). Moreover, YK-4-279 was able to overcome the established chemoresistance of LA-N-6 NB cells. In an orthotopic xenograft NB mouse model, YK-4-279 inhibited NB tumor growth and induced apoptosis in tumor cells through PARP and Caspase 3 cleavage in vivo. While EWS-FLI1 fusion protein is not frequently found in NB, using the R2 public database of neuroblastoma outcome and gene expression, we found that high expression of EWSR1 was associated with poor patient outcome. Knockdown of EWSR1 inhibited the oncogenic potential of neuroblastoma cell lines. Taken together, our results indicate that YK-4-279 might be a promising agent for treatment of NB that merits further exploration.
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