1H MRS identifies specific metabolite profiles associated with MYCN-amplified and non-amplified tumour subtypes of neuroblastoma cell lines.
Neuroblastoma is the most common extracranial solid malignancy in children. The disease possesses a broad range of clinical phenotypes with widely varying prognoses. Numerous studies have sought to identify the associated genetic abnormalities in the tumour, resulting in the identification of useful prognostic markers. In particular, the presence of multiple copies of the MYCN oncogene (referred to as MYCN amplification) has been found to confer a poor prognosis. However, the molecular pathways involved are as yet poorly defined. Metabolite profiles generated by in vitro (1)H MRS provide a means of investigating the downstream metabolic consequences of genetic alterations and can identify potential targets for new agents. Thirteen neuroblastoma cell lines possessing multiple genetic alterations were investigated; seven were MYCN amplified and six MYCN non-amplified. In vitro magic angle spinning (1)H MRS was performed on cell suspensions, and the spectra analysed to obtain metabolite concentration ratios relative to total choline (tCho). A principal component analysis using these concentration ratios showed that MYCN-amplified and non-amplified cell lines form separate classes according to their metabolite profiles. Phosphocholine/tCho and taurine/tCho were found to be significantly raised (p < 0.05) and glycerophosphocholine/tCho significantly reduced (p < 0.05) in the MYCN-amplified compared with the MYCN non-amplified cell lines (two-tailed t test). (1)H MRS of the SH-EP1 cell line and an isogenic cell line transfected with the MYCN oncogene also showed that MYCN oncogene over-expression causes alterations in phosphocholine, glycerophosphocholine and taurine concentrations. Molecular pathways of choline and taurine metabolism are potential targets for new agents tailored to MYCN-amplified neuroblastoma.
Peet
Andrew C
AC
Department of Academic Paediatrics and Child Health, University of Birmingham, Whittall Street, Birmingham B4 6NH, UK. acpeet@doctors.org.uk
McConville
Carmel
C
Wilson
Martin
M
Levine
Barry A
BA
Reed
Michelle
M
Dyer
Sara A
SA
Edwards
Emma C
EC
Strachan
Mary C
MC
McMullan
Dominic J
DJ
Wilkes
Timothy M
TM
Grundy
Richard G
RG
D045744:Cell Line, Tumor; D002794:Choline / Q000378:metabolism; D005784:Gene Amplification; D006801:Humans; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000378:metabolism* / Q000473:pathology*; D009687:Nuclear Proteins / Q000235:genetics*; D015513:Oncogene Proteins / Q000235:genetics*; D025341:Principal Component Analysis
C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D002794:Choline