Abstract 4194: An in-silico approach to identify genes required for polyamine transport

Abstract

Abstract The purpose of this study was to use an in-silico approach to identify genes required for polyamine transport. Polyamines are small positively charged molecules that control vital cellular processes including cell proliferation and growth. Cells obtain polyamines by biosynthesis or transport from the extracellular environment. Cancer cells require high levels of polyamines to sustain rapid growth, and therapies aimed at polyamine depletion are considered promising. The FDA approved drug difluoromethylorthinine (DFMO) blocks polyamine biosynthesis, however, in most cases malignant cells evade the biosynthetic block by increasing transport. Thus, a dual therapy that simultaneously targets polyamine biosynthesis and transport is needed. The mechanism of polyamine transport is poorly understood in multicellular eukaryotes and identification of genes involved in polyamine transport has largely relied on an inefficient hit-or-miss ‘educated guess’ approach. To increase the probability of identifying genes involved in polyamine transport, we adopted an in-silico approach comparing protein-protein interactions with the protein product of the human ATP13A3 gene across multiple databases. We used ATP13A3 because our work, and the work of others, has shown that ATP13A3 and its Drosophila ortholog ‘anne’ are required for polyamine transport. We searched for high confidence protein interactors with ATP13A3 in four databases, BioGRID, STRING, NextProt, and GPS-Prot, prioritizing hits that occurred in more than one database. We next asked if any of the high priority hits had orthologs in Drosophila. We chose to study the candidate genes in Drosophila because we have utilized the sophisticated genetic resources available in this organism to develop novel assays to identify positive and negative regulators of polyamine transport. Using the criteria described, we identified four candidates that occurred in three databases, and one that occurred in two databases. In addition, a very high confidence match to the human gene SLC15A was observed in one database and included in the group of candidate genes. To determine the validity of our candidate gene enrichment approach we are currently testing each gene for roles in polyamine transport. Citation Format: Victoria Millington, Laurence von Kalm. An in-silico approach to identify genes required for polyamine transport [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4194.