Oncotarget

Research Papers:

MYCN amplification confers enhanced folate dependence and methotrexate sensitivity in neuroblastoma

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 and Lesley J. Ashton _

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Oncotarget. 2015; 6:15510-15523. https://doi.org/10.18632/oncotarget.3732

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Abstract

Diana T. Lau1, Claudia L. Flemming1, Samuele Gherardi2, Giovanni Perini2, André Oberthuer3, Matthias Fischer3, Dilafruz Juraeva4, Benedikt Brors4, Chengyuan Xue1, Murray D. Norris1, Glenn M. Marshall1,5, Michelle Haber1, Jamie I. Fletcher1,* and Lesley J. Ashton6,*

1 Children’s Cancer Institute Australia, Lowy Cancer Research Centre, Randwick, NSW, Australia

2 Department of Biology, University of Bologna, Bologna, Italy

3 Children’s Hospital, Department of Pediatric Oncology and Hematology, University of Cologne and Centre for Molecular Medicine Cologne, Cologne, Germany

4 Division of Theoretical Bioinformatics, German Cancer Research Center, Heidelberg, Germany

5 Kids Cancer Centre, Sydney Children’s Hospital, Randwick, NSW, Australia

6 Faculty of Medicine, School of Women’s and Children’s Health, University of New South Wales, Sydney, NSW, Australia and Research Portfolio, University of Sydney, Sydney, NSW, Australia

* These authors have contributed equally to this work

Correspondence to:

Jamie I. Fletcher, email:

Lesley J. Ashton, email:

Keywords: MYCN, MYC, SLC19A1, methotrexate, neuroblastoma

Received: February 10, 2015 Accepted: March 10, 2015 Published: March 30, 2015

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.


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