The polyamine transporter ATP13A3 mediates DFMO-induced polyamine uptake in neuroblastoma

High-risk neuroblastomas, often associated with MYCN oncogene amplification, are addicted to polyamines, small polycations vital for cellular functioning. We have shown that neuroblastoma cells increase polyamine uptake when exposed to the polyamine biosynthesis inhibitor DFMO, currently in clinical trial, and that this mechanism limits the efficacy of the drug. While this finding resulted in the clinical development of polyamine transport inhibitors including AMXT 1501, presently under clinical investigation in combination with DFMO, the mechanisms and transporters involved in DFMO-induced polyamine uptake are unknown. Knockdown of ATP13A3, a member of the P5B-ATPase family, limited basal and DFMO-induced polyamine uptake, attenuated MYCN-amplified and non-MYCN-amplified neuroblastoma cell growth and potentiated the inhibitory effects of DFMO. Overexpression of ATP13A3 in neuroblastoma cells increased polyamine uptake, which was inhibited by AMXT 1501, highlighting ATP13A3 as a key target of the drug. The association between high ATP13A3 expression and poorer survival in neuroblastoma further supports a role of this transporter in neuroblastoma progression. Thus, this study identified ATP13A3 as a critical regulator of basal and DFMO-induced polyamine uptake and a novel therapeutic target for neuroblastoma. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=186 SRC="FIGDIR/small/581161v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@11bef78org.highwire.dtl.DTLVardef@106c250org.highwire.dtl.DTLVardef@bf39b1org.highwire.dtl.DTLVardef@64d05f_HPS_FORMAT_FIGEXP M_FIG C_FIG