MYCN amplification confers enhanced folate dependence and methotrexate sensitivity in neuroblastoma.

Abstract

MYCN amplification occurs in 20% of neuroblastomas and is strongly related to poor clinical outcome. We have identified folate-mediated one-carbon metabolism as highly upregulated in neuroblastoma tumors with MYCN amplification and have validated this finding experimentally by showing that MYCN amplified neuroblastoma cell lines have a higher requirement for folate and are significantly more sensitive to the antifolate methotrexate than cell lines without MYCN amplification. We have demonstrated that methotrexate uptake in neuroblastoma cells is mediated principally by the reduced folate carrier (RFC; SLC19A1), that SLC19A1 and MYCN expression are highly correlated in both patient tumors and cell lines, and that SLC19A1 is a direct transcriptional target of N-Myc. Finally, we assessed the relationship between SLC19A1 expression and patient survival in two independent primary tumor cohorts and found that SLC19A1 expression was associated with increased risk of relapse or death, and that SLC19A1 expression retained prognostic significance independent of age, disease stage and MYCN amplification. This study adds upregulation of folate-mediated one-carbon metabolism to the known consequences of MYCN amplification, and suggests that this pathway might be targeted in poor outcome tumors with MYCN amplification and high SLC19A1 expression.

• Authors: Diana T Lau, Claudia L Flemming, Samuele Gherardi, Giovanni Perini, André Oberthuer, Matthias Fischer, Dilafruz Juraeva, Benedikt Brors, Chengyuan Xue, Murray D Norris, Glenn M Marshall, Michelle Haber, Jamie I Fletcher, Lesley J Ashton
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 17 Pg. 15510-23 (Jun 20 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 25860940 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Folic Acid Antagonists
• Intracellular Signaling Peptides and Proteins
• MYCN protein, human
• N-Myc Proto-Oncogene Protein
• NMI protein, human
• Nuclear Proteins
• Oncogene Proteins
• RNA, Messenger
• Reduced Folate Carrier Protein
• SLC19A1 protein, human
• Folic Acid
• Methotrexate

Topics

• Cell Line, Tumor
• Folic Acid (metabolism)
• Folic Acid Antagonists (pharmacology)
• Gene Amplification
• Gene Expression Regulation, Neoplastic
• Humans
• Intracellular Signaling Peptides and Proteins (metabolism)
• Methotrexate (pharmacology)
• N-Myc Proto-Oncogene Protein
• Neuroblastoma (genetics, mortality, pathology)
• Nuclear Proteins (genetics, metabolism)
• Oncogene Proteins (genetics, metabolism)
• RNA, Messenger (biosynthesis)
• Reduced Folate Carrier Protein (metabolism)