Abstract 1453: SLC25A32 sustains cancer cell proliferation by regulating flavin adenine dinucleotide (FAD) metabolism

Abstract

Abstract SLC25A32 is a member of the solute carrier 25 family of mitochondrial transporters. SLC25A32 transports tetrahydrofolate (THF) as well as FAD into mitochondria and regulates mitochondrial one-carbon metabolism and redox balance. While it is known that cancer cells require one-carbon and FAD-dependent mitochondrial metabolism for generation of nucleotides, lipids and for maintenance of redox homeostasis to sustain growth, the role of SLC25A32 in cancer cell survival remains unexplored. Our results indicate that the SLC25A32 gene is highly amplified in different tumors and that its amplification correlates with increased mRNA expression and with reduced patient survival. SiRNA-mediated knock-down and CRISPR-mediated knock-out of SLC25A32 in cancer cells of different origins, resulted in the identification of sensitive and resistant cells to SLC25A32 inhibition. Mechanistically, tracing of deuterated serine upon SLC25A32 knock-down did not affect the mitochondrial/cytosolic folate flux as measured by Liquid Chromatography coupled Mass Spectrometry (LC-MS). Instead, SLC25A32 inhibition resulted in respiratory chain dysfunction at the FAD-dependent complex II enzyme, induction of Reactive Oxygen Species (ROS) and depletion of reduced glutathione (GSH), impairing cancer cell proliferation. Moreover, Buthionine sulfoximine (BSO) treatment further sensitized cells to ROS-mediated inhibition of cell proliferation upon SLC25A32 knock-down. Treatment of cells with the FAD precursor riboflavin and with GSH rescued cancer cell proliferation upon SLC25A32 down-regulation. Our results indicate that inhibition of mitochondrial FAD transport by targeting SLC25A32 has potential clinical applications as a single agent or in combination with approved cancer drugs that lead to increased oxidative stress and reduced tumor growth. Citation Format: Valeria Santoro, Ilya Kovalenko, Kim Vriens, Stefan Christen, Andreas Bernthaler, Andrea Haegebarth, Sarah-Maria Fendt, Sven Christian. SLC25A32 sustains cancer cell proliferation by regulating flavin adenine dinucleotide (FAD) metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1453.