Antioxidant inhibition of steady-state reactive oxygen species and cell growth in neuroblastoma. Surgery 2015 Sep;158(3):827-36
Date
06/20/2015Pubmed ID
26088922Pubmed Central ID
PMC4536094DOI
10.1016/j.surg.2015.03.062Scopus ID
2-s2.0-84938984299 (requires institutional sign-in at Scopus site) 8 CitationsAbstract
BACKGROUND: Reactive oxygen species (ROS) contribute to adult tumorigenesis; however, their roles in pediatric solid tumors are unknown. Here, we sought to define the steady-state ROS levels in neuroblastoma and to examine whether aggressive cellular behavior, which may predict treatment failure, is regulated by ROS.
METHODS: Neuroblastoma sections were assessed for 4-hydroxynonenal (4-HNE), a marker of intracellular lipid peroxidation and a byproduct of increased levels of ROS. Human neuroblastoma cell lines, MYCN-amplified BE(2)-C and MYCN-nonamplified SK-N-SH, were examined in our study. Superoxide and hydroperoxide oxidation products were detected by staining for dihydroethidium (DHE) and 5, 6-carboxy-2', 7'-dichlorodihydrofluorescein diacetate (CDCFH2), using the oxidation-insensitive analog CDCF as a negative control. Cells were treated with N-acetylcysteine (NAC; 10 mmol/L) daily for 5 days and analyzed.
RESULTS: Greater expression of 4-HNE was observed in undifferentiated tumor sections as compared with the more differentiated tumors. Interestingly, increased levels of ROS were detected in MYCN-amplified BE(2)-C cells. Moreover, gastrin-releasing peptide receptor-induced ROS production stimulated upregulation of the hypoxia inducible factor (HIF)-1α/vascular endothelial growth factor (VEGF) pathway and an increase in cell growth. Antioxidant NAC decreased HIF-1α/VEGF expression and inhibited BE(2)-C cell growth.
CONCLUSION: We report a novel observation that shifting the redox balance toward greater ROS levels results in a more aggressive neuroblastoma phenotype. Our data suggest that ROS play a critical role in refractory neuroblastoma.
Author List
Zhu Y, Paul P, Lee S, Craig BT, Rellinger EJ, Qiao J, Gius DR, Chung DHAuthor
Brian T. Craig MD Assistant Professor in the Surgery department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AcetylcysteineAntioxidants
Biomarkers, Tumor
Blotting, Western
Cell Line, Tumor
Cell Proliferation
Humans
Immunohistochemistry
Neuroblastoma
Reactive Oxygen Species
