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Abstract A12: Tumorigenic proteins upregulated in pediatric neuroblastoma MYCN-amplified tumorspheres confer radiotherapy resistance

2018; American Association for Cancer Research; Volume: 78; Issue: 19_Supplement Linguagem: Inglês

10.1158/1538-7445.pedca17-a12

1538-7445

Tamara Mary Abou-Antoun, Jad Abdallah, George Antoun Khazen, Zeina Nasr, Anthony D. Sandler,

Cancer, Hypoxia, and Metabolism

Abstract Neuroblastoma is one of the most common extracranial central nervous system cancers of infancy with high mortality in children. We used SILAC proteomics to analyze the protein expression of the MYCN-amplified (IMR-32) and non-MYCN-amplified (SK-N-SH) human neuroblastoma stem-like tumorspheres after radiotherapy. More than 3,500 proteins were differentially expressed between the two cell types, and importantly many proteins were significantly upregulated in the IMR-32 compared to the SK-N-SH tumorspheres after radiotherapy, including the highly tumorigenic HSP90B (8-fold), prohibitin (4-fold), HMGA1 (15-fold), and FABP5 (3-fold). The top canonical pathways that the majority of the upregulated proteins in the neuroblastoma IMR-32 stem-like tumorspheres mapped to after radiotherapy included Actin Nucleation by ARP-WASP Complex; Signaling by Rho Family GTPases; Integrin Signaling; Cdc42 Signaling; and RhoGDI Signaling pathways. The associated network functions affiliated with these proteins were primarily cell death and survival, cell morphology, cellular function and maintenance; cell signaling, post-translational modification and protein synthesis; RNA post-transcriptional modification, molecular transport, RNA trafficking, and cancer. We sought to determine whether transcriptional knockdown of HMGA1 and FABP5 would radiosensitize these tumorspheres, as assessed by measuring the rate of cellular cytotoxicity, proliferation, and migration. IMR-32 neuroblastoma tumorspheres with transcriptional knockdown of HMGA1 and FABP5 exhibited lower rates of proliferation and migration, while cellular cytotoxicity was enhanced after 2Gy radiotherapy compared to nontransfected counterparts. Our finding suggests that HMGA1 and FABP5 may be contributing to the radiotherapy resistance of MYCN-amplified IMR-32 stem-like tumorspheres. Therapeutic resistance in the aggressive, MYCN-amplified high-risk group of pediatric neuroblastoma may be due to the upregulation of these highly tumorigenic proteins that are conferring protective mechanisms to this deadly childhood cancer. Citation Format: Tamara Mary Abou-Antoun, Jad Helmi Abdallah, George Antoun Khazen, Zeina Nasr, Anthony Sandler. Tumorigenic proteins upregulated in pediatric neuroblastoma MYCN-amplified tumorspheres confer radiotherapy resistance [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr A12.