The polyamine transporter ATP13A3 mediates difluoromethylornithine‐induced polyamine uptake in neuroblastoma
High‐risk neuroblastomas, often associated with MYCN protooncogene amplification, are addicted to polyamines, small polycations vital for cellular functioning. We have previously shown that neuroblastoma cells increase polyamine uptake when exposed to the polyamine biosynthesis inhibitor difluoromet...
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| Format: | Article |
| Language: | English |
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Wiley
2025-03-01
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| Series: | Molecular Oncology |
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| Online Access: | https://doi.org/10.1002/1878-0261.13789 |
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| author | Mujahid Azfar Weiman Gao Chris Van den Haute Lin Xiao Mawar Karsa Ruby Pandher Ayu Karsa Dayna Spurling Emma Ronca Angelika Bongers Xinyi Guo Chelsea Mayoh Youri Fayt Arthur Schoofs Mark R. Burns Steven H. L. Verhelst Murray D. Norris Michelle Haber Peter Vangheluwe Klaartje Somers |
| author_facet | Mujahid Azfar Weiman Gao Chris Van den Haute Lin Xiao Mawar Karsa Ruby Pandher Ayu Karsa Dayna Spurling Emma Ronca Angelika Bongers Xinyi Guo Chelsea Mayoh Youri Fayt Arthur Schoofs Mark R. Burns Steven H. L. Verhelst Murray D. Norris Michelle Haber Peter Vangheluwe Klaartje Somers |
| author_sort | Mujahid Azfar |
| collection | DOAJ |
| description | High‐risk neuroblastomas, often associated with MYCN protooncogene amplification, are addicted to polyamines, small polycations vital for cellular functioning. We have previously shown that neuroblastoma cells increase polyamine uptake when exposed to the polyamine biosynthesis inhibitor difluoromethylornithine (DFMO), and this mechanism is thought to limit the efficacy of the drug in clinical trials. This finding resulted in the clinical development of polyamine transport inhibitors, including AMXT 1501, which is presently under clinical investigation in combination with DFMO. However, the mechanisms and transporters involved in DFMO‐induced polyamine uptake are unknown. Here, we report that knockdown of ATPase 13A3 (ATP13A3), a member of the P5B‐ATPase polyamine transporter 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. Conversely, overexpression of ATP13A3 in neuroblastoma cells increased polyamine uptake, which was inhibited by AMXT 1501, highlighting ATP13A3 as a key target of the drug. An association between high ATP13A3 expression and poor 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. |
| format | Article |
| id | doaj-art-b308c7bf3a7e49149a0178f5e8bddd0b |
| institution | DOAJ |
| issn | 1574-7891 1878-0261 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj-art-b308c7bf3a7e49149a0178f5e8bddd0b2025-08-20T03:06:08ZengWileyMolecular Oncology1574-78911878-02612025-03-0119391393610.1002/1878-0261.13789The polyamine transporter ATP13A3 mediates difluoromethylornithine‐induced polyamine uptake in neuroblastomaMujahid Azfar0Weiman Gao1Chris Van den Haute2Lin Xiao3Mawar Karsa4Ruby Pandher5Ayu Karsa6Dayna Spurling7Emma Ronca8Angelika Bongers9Xinyi Guo10Chelsea Mayoh11Youri Fayt12Arthur Schoofs13Mark R. Burns14Steven H. L. Verhelst15Murray D. Norris16Michelle Haber17Peter Vangheluwe18Klaartje Somers19Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine KU Leuven BelgiumChildren's Cancer Institute, Lowy Cancer Research Centre UNSW Sydney AustraliaGroup for Neurobiology and Gene Therapy KU Leuven BelgiumChildren's Cancer Institute, Lowy Cancer Research Centre UNSW Sydney AustraliaChildren's Cancer Institute, Lowy Cancer Research Centre UNSW Sydney AustraliaChildren's Cancer Institute, Lowy Cancer Research Centre UNSW Sydney AustraliaChildren's Cancer Institute, Lowy Cancer Research Centre UNSW Sydney AustraliaChildren's Cancer Institute, Lowy Cancer Research Centre UNSW Sydney AustraliaChildren's Cancer Institute, Lowy Cancer Research Centre UNSW Sydney AustraliaChildren's Cancer Institute, Lowy Cancer Research Centre UNSW Sydney AustraliaChildren's Cancer Institute, Lowy Cancer Research Centre UNSW Sydney AustraliaChildren's Cancer Institute, Lowy Cancer Research Centre UNSW Sydney AustraliaLaboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine KU Leuven BelgiumLaboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine KU Leuven BelgiumAminex Therapeutics Aminex Therapeutics Inc. Kirkland WA USALaboratory of Chemical Biology, Department of Cellular and Molecular Medicine KU Leuven BelgiumChildren's Cancer Institute, Lowy Cancer Research Centre UNSW Sydney AustraliaChildren's Cancer Institute, Lowy Cancer Research Centre UNSW Sydney AustraliaLaboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine KU Leuven BelgiumChildren's Cancer Institute, Lowy Cancer Research Centre UNSW Sydney AustraliaHigh‐risk neuroblastomas, often associated with MYCN protooncogene amplification, are addicted to polyamines, small polycations vital for cellular functioning. We have previously shown that neuroblastoma cells increase polyamine uptake when exposed to the polyamine biosynthesis inhibitor difluoromethylornithine (DFMO), and this mechanism is thought to limit the efficacy of the drug in clinical trials. This finding resulted in the clinical development of polyamine transport inhibitors, including AMXT 1501, which is presently under clinical investigation in combination with DFMO. However, the mechanisms and transporters involved in DFMO‐induced polyamine uptake are unknown. Here, we report that knockdown of ATPase 13A3 (ATP13A3), a member of the P5B‐ATPase polyamine transporter 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. Conversely, overexpression of ATP13A3 in neuroblastoma cells increased polyamine uptake, which was inhibited by AMXT 1501, highlighting ATP13A3 as a key target of the drug. An association between high ATP13A3 expression and poor 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.https://doi.org/10.1002/1878-0261.13789neuroblastomaDFMOATP13A3AMXT 1501polyamine depletionpolyamine transport inhibitor |
| spellingShingle | Mujahid Azfar Weiman Gao Chris Van den Haute Lin Xiao Mawar Karsa Ruby Pandher Ayu Karsa Dayna Spurling Emma Ronca Angelika Bongers Xinyi Guo Chelsea Mayoh Youri Fayt Arthur Schoofs Mark R. Burns Steven H. L. Verhelst Murray D. Norris Michelle Haber Peter Vangheluwe Klaartje Somers The polyamine transporter ATP13A3 mediates difluoromethylornithine‐induced polyamine uptake in neuroblastoma Molecular Oncology neuroblastoma DFMO ATP13A3 AMXT 1501 polyamine depletion polyamine transport inhibitor |
| title | The polyamine transporter ATP13A3 mediates difluoromethylornithine‐induced polyamine uptake in neuroblastoma |
| title_full | The polyamine transporter ATP13A3 mediates difluoromethylornithine‐induced polyamine uptake in neuroblastoma |
| title_fullStr | The polyamine transporter ATP13A3 mediates difluoromethylornithine‐induced polyamine uptake in neuroblastoma |
| title_full_unstemmed | The polyamine transporter ATP13A3 mediates difluoromethylornithine‐induced polyamine uptake in neuroblastoma |
| title_short | The polyamine transporter ATP13A3 mediates difluoromethylornithine‐induced polyamine uptake in neuroblastoma |
| title_sort | polyamine transporter atp13a3 mediates difluoromethylornithine induced polyamine uptake in neuroblastoma |
| topic | neuroblastoma DFMO ATP13A3 AMXT 1501 polyamine depletion polyamine transport inhibitor |
| url | https://doi.org/10.1002/1878-0261.13789 |
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