PMID- 29539615 OWN - NLM STAT- MEDLINE DCOM- 20180612 LR - 20191210 IS - 1423-0232 (Electronic) IS - 0030-2414 (Linking) VI - 94 IP - 6 DP - 2018 TI - Epidermal Growth Factor Receptor Regulation of Ewing Sarcoma Cell Function. PG - 383-393 LID - 10.1159/000487143 [doi] AB - OBJECTIVE: Ewing sarcoma (ES) is a type of childhood cancer probably arising from stem mesenchymal or neural crest cells. The epidermal growth factor receptor (EGFR) acts as a driver oncogene in many types of solid tumors. However, its involvement in ES remains poorly understood. METHODS: Human SK-ES-1 and RD-ES ES cells were treated with EGF, the EGFR inhibitor tyrphostin (AG1478), or phosphoinositide 3-kinase (PI3K) or extracellular-regulated kinase (ERK)/mitogen-activated kinase (MAPK) inhibitors. Cell proliferation survival, cycle, and senescence were analyzed. The protein content of possible targets of EGFR manipulation was measured by Western blot. RESULTS: Cell proliferation and survival were increased by EGF and inhibited by AG1478. The EGFR inhibitor also altered the cell cycle, inducing arrest in G1 and increasing the sub-G1 population, reduced polyploidy and increased the population of senescent cells. In addition, AG1478 reduced the levels of phosphorylated AKT (p-AKT), ERK, p-ERK, cyclin D1, and brain-derived neurotrophic factor (BDNF), while enhancing p53 levels. Cell proliferation was also impaired by inhibitors of PI3K or ERK, alone or combined with AG1478. CONCLUSIONS: Our findings reveal novel aspects of EGFR regulation of ES cells and provide early evidence for antitumor activities of EGFR inhibitors in ES. CI - (c) 2018 S. Karger AG, Basel. FAU - Kersting, Nathalia AU - Kersting N AD - Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE HCPA), Porto Alegre, Brazil. FAU - Kunzler Souza, Barbara AU - Kunzler Souza B AD - Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE HCPA), Porto Alegre, Brazil. FAU - Araujo Vieira, Igor AU - Araujo Vieira I AD - Laboratory of Genomic Medicine, Experimental Research Center, Clinical Hospital (CPE-HCPA), Porto Alegre, Brazil. FAU - Pereira Dos Santos, Rafael AU - Pereira Dos Santos R AD - Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE HCPA), Porto Alegre, Brazil. AD - Department of Pharmacology, Institute for Basic Health Sciences, Porto Alegre, Brazil. FAU - Brufatto Olguins, Danielly AU - Brufatto Olguins D AD - Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE HCPA), Porto Alegre, Brazil. FAU - Jose Gregianin, Lauro AU - Jose Gregianin L AD - Department of Pediatrics, Faculty of Medicine, Porto Alegre, Brazil. AD - Pediatric Oncology Service, Clinical Hospital, Federal University of Rio Grande do Sul, Porto Alegre, Brazil. FAU - Tesainer Brunetto, Andre AU - Tesainer Brunetto A AD - Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE HCPA), Porto Alegre, Brazil. AD - Rafael Koff Acordi Research Center, Children's Cancer Institute, Porto Alegre, Brazil. FAU - Lunardi Brunetto, Algemir AU - Lunardi Brunetto A AD - Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE HCPA), Porto Alegre, Brazil. AD - Rafael Koff Acordi Research Center, Children's Cancer Institute, Porto Alegre, Brazil. FAU - Roesler, Rafael AU - Roesler R AD - Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE HCPA), Porto Alegre, Brazil. AD - Department of Pharmacology, Institute for Basic Health Sciences, Porto Alegre, Brazil. FAU - Brunetto de Farias, Caroline AU - Brunetto de Farias C AD - Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE HCPA), Porto Alegre, Brazil. AD - Rafael Koff Acordi Research Center, Children's Cancer Institute, Porto Alegre, Brazil. FAU - Schwartsmann, Gilberto AU - Schwartsmann G AD - Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE HCPA), Porto Alegre, Brazil. AD - Department of Internal Medicine, Faculty of Medicine, Federal University of Rio Grande do Sul, Porto Alegre, Brazil. LA - eng PT - Journal Article DEP - 20180314 PL - Switzerland TA - Oncology JT - Oncology JID - 0135054 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (CCND1 protein, human) RN - 0 (Enzyme Inhibitors) RN - 0 (Phosphoinositide-3 Kinase Inhibitors) RN - 0 (Quinazolines) RN - 0 (Tumor Suppressor Protein p53) RN - 0 (Tyrphostins) RN - 136601-57-5 (Cyclin D1) RN - 170449-18-0 (RTKI cpd) RN - 62229-50-9 (Epidermal Growth Factor) RN - 7171WSG8A2 (BDNF protein, human) RN - EC 2.7.10.1 (EGFR protein, human) RN - EC 2.7.10.1 (ErbB Receptors) RN - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases) SB - IM MH - Bone Neoplasms/*pathology MH - Brain-Derived Neurotrophic Factor/metabolism MH - Cell Line, Tumor MH - Cell Proliferation/*drug effects MH - Cyclin D1/metabolism MH - Enzyme Inhibitors/*pharmacology MH - Epidermal Growth Factor/pharmacology MH - ErbB Receptors/antagonists & inhibitors/*metabolism MH - Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors MH - G1 Phase Cell Cycle Checkpoints/drug effects MH - Humans MH - Phosphoinositide-3 Kinase Inhibitors MH - Phosphorylation/drug effects MH - Quinazolines/*pharmacology MH - Sarcoma, Ewing/*pathology MH - Signal Transduction/drug effects MH - Tumor Suppressor Protein p53/metabolism MH - Tyrphostins/*pharmacology OTO - NOTNLM OT - Cell cycle OT - Cell proliferation OT - Epidermal growth factor receptor OT - Ewing sarcoma OT - Extracellular signal-regulated kinase OT - Phosphoinositide 3-kinase EDAT- 2018/03/15 06:00 MHDA- 2018/06/13 06:00 CRDT- 2018/03/15 06:00 PHST- 2017/08/23 00:00 [received] PHST- 2018/01/10 00:00 [accepted] PHST- 2018/03/15 06:00 [pubmed] PHST- 2018/06/13 06:00 [medline] PHST- 2018/03/15 06:00 [entrez] AID - 000487143 [pii] AID - 10.1159/000487143 [doi] PST - ppublish SO - Oncology. 2018;94(6):383-393. doi: 10.1159/000487143. Epub 2018 Mar 14.