Abstract 2495: Sepiapterin reductase interacts with Ornithine Decarboxylase and regulates neuroblastoma proliferation

Abstract

Abstract Ornithine Decarboxylase (ODC) is a key, rate-limiting enzyme in mammalian polyamine biosynthesis that is upregulated in various types of cancer including neuroblastoma (NB). MYCN is a transcription factor and proto-oncogene that has been shown to be a key prognostic factor associated with advanced stage NB. ODC is a transcriptional target of MYCN, and has been found to play a critical role in NB progression. Previous studies have shown that inhibition of ODC through drugs such as alpha-difluoromethylornithine (DFMO) depletes intracellular polyamine pools and induces G1 cell cycle arrest. Our previous studies have shown that the anti-proliferative effect of DFMO in NB involves upregulation of the cyclin dependent kinase inhibitor p27 and downregulation of MYCN. In a search for novel regulators of ODC, we recently discovered that sepiapterin reductase (SPR), a key enzyme in the biosynthesis of tetrahydrobiopterin, binds to ODC and may regulate ODC activity through a novel mechanism. Co-immunoprecipitation experiments using NB cell lysates show that ODC interacts with SPR. In addition, immunofluorescence staining and laser-scanning confocal microscopy confirm the co-localization of ODC and SPR. Furthermore, downregulation of SPR expression using siRNA targeting SPR results in significant inhibition of NB proliferation, without affecting ODC protein levels. These results suggest that the interaction between SPR and ODC may be critically important to ODC activity and function and may constitute a novel mechanism for the regulation of NB proliferation. This interaction may play a critical role in fundamental physiological and pathophysiological processes including the development and progression of NB. Understanding the novel interaction between ODC and SPR might play a crucial role for the development of new drugs targeting SPR for the treatment of NB and other MYC/ODC-driven diseases. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2495. doi:1538-7445.AM2012-2495