Gamble, Laura D., Purgato, Stefania, Murray, Jayne, Xiao, Lin ORCID: 0000-0001-7258-5333, Yu, Denise M. T., Hanssen, Kimberley M., Giorgi, Federico M. ORCID: 0000-0002-7325-9908, Carter, Daniel R., Gifford, Andrew J., Valli, Emanuele ORCID: 0000-0002-0928-8624, Milazzo, Giorgio ORCID: 0000-0002-1930-4763, Kamili, Alvin ORCID: 0000-0002-4864-1195, Mayoh, Chelsea, Liu, Bing, Eden, Georgina, Sarraf, Sara, Allan, Sophie, Di Giacomo, Simone, Flemming, Claudia L., Russell, Amanda J., Cheung, Belamy B., Oberthuer, Andre, London, Wendy B., Fischer, Matthias, Trahair, Toby N., Fletcher, Jamie, I, Marshall, Glenn M., Ziegler, David S., Hogarty, Michael D., Burns, Mark R., Perini, Giovanni, Norris, Murray D. and Haber, Michelle ORCID: 0000-0003-2036-8817 (2019). Inhibition of polyamine synthesis and uptake reduces tumor progression and prolongs survival in mouse models of neuroblastoma. Sci. Transl. Med., 11 (477). WASHINGTON: AMER ASSOC ADVANCEMENT SCIENCE. ISSN 1946-6242

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Abstract

Amplification of the MYCN oncogene is associated with an aggressive phenotype and poor outcome in childhood neuroblastoma. Polyamines are highly regulated essential cations that are frequently elevated in cancer cells, and the rate-limiting enzyme in polyamine synthesis, ornithine decarboxylase 1 (ODC1), is a direct transcriptional target of MYCN. Treatment of neuroblastoma cells with the ODC1 inhibitor difluoromethylornithine (DFMO), although a promising therapeutic strategy, is only partially effective at impeding neuroblastoma cell growth due to activation of compensatory mechanisms resulting in increased polyamine uptake from the surrounding microenvironment. In this study, we identified solute carrier family 3 member 2 (SLC3A2) as the key transporter involved in polyamine uptake in neuroblastoma. Knockdown of SLC3A2 in neuroblastoma cells reduced the uptake of the radiolabeled polyamine spermidine, and DFMO treatment increased SLC3A2 protein. In addition, MYCN directly increased polyamine synthesis and promoted neuroblastoma cell proliferation by regulating SLC3A2 and other regulatory components of the polyamine pathway. Inhibiting polyamine uptake with the small-molecule drug AMXT 1501, in combination with DFMO, prevented or delayed tumor development in neuroblastoma-prone mice and extended survival in rodent models of established tumors. Our findings suggest that combining AMXT 1501 and DFMO with standard chemotherapy might be an effective strategy for treating neuroblastoma.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Gamble, Laura D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Purgato, StefaniaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Murray, JayneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Xiao, LinUNSPECIFIEDorcid.org/0000-0001-7258-5333UNSPECIFIED
Yu, Denise M. T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hanssen, Kimberley M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Giorgi, Federico M.UNSPECIFIEDorcid.org/0000-0002-7325-9908UNSPECIFIED
Carter, Daniel R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gifford, Andrew J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Valli, EmanueleUNSPECIFIEDorcid.org/0000-0002-0928-8624UNSPECIFIED
Milazzo, GiorgioUNSPECIFIEDorcid.org/0000-0002-1930-4763UNSPECIFIED
Kamili, AlvinUNSPECIFIEDorcid.org/0000-0002-4864-1195UNSPECIFIED
Mayoh, ChelseaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Liu, BingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eden, GeorginaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sarraf, SaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Allan, SophieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Di Giacomo, SimoneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Flemming, Claudia L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Russell, Amanda J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cheung, Belamy B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Oberthuer, AndreUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
London, Wendy B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fischer, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Trahair, Toby N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fletcher, Jamie, IUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marshall, Glenn M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ziegler, David S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hogarty, Michael D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Burns, Mark R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Perini, GiovanniUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Norris, Murray D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Haber, MichelleUNSPECIFIEDorcid.org/0000-0003-2036-8817UNSPECIFIED
URN: urn:nbn:de:hbz:38-158775
DOI: 10.1126/scitranslmed.aau1099
Journal or Publication Title: Sci. Transl. Med.
Volume: 11
Number: 477
Date: 2019
Publisher: AMER ASSOC ADVANCEMENT SCIENCE
Place of Publication: WASHINGTON
ISSN: 1946-6242
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
AMINO-ACID-TRANSPORT; ORNITHINE-DECARBOXYLASE; N-MYC; CANCER; EXPRESSION; DIFLUOROMETHYLORNITHINE; CHEMOPREVENTION; BIOSYNTHESIS; SLC3A2; CD98Multiple languages
Cell Biology; Medicine, Research & ExperimentalMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/15877

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