Universität zu Köln

Lau, Diana T., Flemming, Claudia L., Gherardi, Samuele, Perini, Giovanni, Oberthuer, Andre, Fischer, Matthias, Juraeva, Dilafruz, Brors, Benedikt ORCID: 0000-0001-5940-3101, Xue, Chengyuan, Norris, Murray D., Marshall, Glenn M., Haber, Michelle ORCID: 0000-0003-2036-8817, Fletcher, Jamie I. and Ashton, Lesley J. (2015). MYCN amplification confers enhanced folate dependence and methotrexate sensitivity in neuroblastoma. Oncotarget, 6 (17). S. 15510 - 15524. ORCHARD PARK: IMPACT JOURNALS LLC. ISSN 1949-2553

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Lau, Diana T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Flemming, Claudia L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Gherardi, Samuele UNSPECIFIED UNSPECIFIED UNSPECIFIED Perini, Giovanni UNSPECIFIED UNSPECIFIED UNSPECIFIED Oberthuer, Andre UNSPECIFIED UNSPECIFIED UNSPECIFIED Fischer, Matthias UNSPECIFIED UNSPECIFIED UNSPECIFIED Juraeva, Dilafruz UNSPECIFIED UNSPECIFIED UNSPECIFIED Brors, Benedikt UNSPECIFIED orcid.org/0000-0001-5940-3101 UNSPECIFIED Xue, Chengyuan UNSPECIFIED UNSPECIFIED UNSPECIFIED Norris, Murray D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Marshall, Glenn M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Haber, Michelle UNSPECIFIED orcid.org/0000-0003-2036-8817 UNSPECIFIED Fletcher, Jamie I. UNSPECIFIED UNSPECIFIED UNSPECIFIED Ashton, Lesley J. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-400976
DOI:	10.18632/oncotarget.3732
Journal or Publication Title:	Oncotarget
Volume:	6
Number:	17
Page Range:	S. 15510 - 15524
Date:	2015
Publisher:	IMPACT JOURNALS LLC
Place of Publication:	ORCHARD PARK
ISSN:	1949-2553
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language N-MYC; C-MYC; GENE-EXPRESSION; ORNITHINE-DECARBOXYLASE; CANCER; PATHWAY; ENZYMES; BIOLOGY; POLYMORPHISMS; PROGRESSION Multiple languages Oncology; Cell Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/40097