Positron emission tomography imaging of the sodium iodide symporter senses real-time energy stress in vivo

Cancer & Metabolism

Research

Piotr Dzien¹  Colin Nixon¹  Agata Mackintosh¹  Gavin Brown¹  Gaurav Malviya¹  Dmitry Soloviev¹  Emma Johnson¹  David Y. Lewis²  Karen Blyth²  Scott K. Lyons³  Oliver Maddocks⁴  Alejandro Huerta Uribe⁴ 

[1] Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, G61 1BD, Glasgow, UK;Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, G61 1BD, Glasgow, UK;School of Cancer Sciences, University of Glasgow, G61 1QH, Glasgow, UK;Cold Spring Harbor Laboratory, 1 Bungtown Road, 11724, Cold Spring Harbor, NY, USA;School of Cancer Sciences, University of Glasgow, G61 1QH, Glasgow, UK;

关键词: Positron emission tomography;    Reporter genes;    Metabolic sensor;    Energy charge;    2-DG;    Oligomycin A;    IACS-010759;   

DOI  :  10.1186/s40170-023-00314-2

 received in 2022-09-29, accepted in 2023-08-15,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundTissue environment is critical in determining tumour metabolic vulnerability. However, in vivo drug testing is slow and waiting for tumour growth delay may not be the most appropriate endpoint for metabolic treatments. An in vivo method for measuring energy stress would rapidly determine tumour targeting in a physiologically relevant environment. The sodium-iodide symporter (NIS) is an imaging reporter gene whose protein product co-transports sodium and iodide, and positron emission tomography (PET) radiolabelled anions into the cell. Here, we show that PET imaging of NIS-mediated radiotracer uptake can rapidly visualise tumour energy stress within minutes following in vivo treatment.MethodsWe modified HEK293T human embryonic kidney cells, and A549 and H358 lung cancer cells to express transgenic NIS. Next, we subjected these cells and implanted tumours to drugs known to induce metabolic stress to observe the impact on NIS activity and energy charge. We used [18F]tetrafluoroborate positron emission tomography (PET) imaging to non-invasively image NIS activity in vivo.ResultsNIS activity was ablated by treating HEK293T cells in vitro, with the Na+/K+ ATPase inhibitor digoxin, confirming that radiotracer uptake was dependent on the sodium–potassium concentration gradient. NIS-mediated radiotracer uptake was significantly reduced (− 58.2%) following disruptions to ATP re-synthesis by combined glycolysis and oxidative phosphorylation inhibition in HEK293T cells and by oxidative phosphorylation inhibition (− 16.6%) in A549 cells in vitro. PET signal was significantly decreased (− 56.5%) within 90 min from the onset of treatment with IACS-010759, an oxidative phosphorylation inhibitor, in subcutaneous transgenic A549 tumours in vivo, showing that NIS could rapidly and sensitively detect energy stress non-invasively, before more widespread changes to phosphorylated AMP-activated protein kinase, phosphorylated pyruvate dehydrogenase, and GLUT1 were detectable.ConclusionsNIS acts as a rapid metabolic sensor for drugs that lead to ATP depletion. PET imaging of NIS could facilitate in vivo testing of treatments targeting energetic pathways, determine drug potency, and expedite metabolic drug development.

【 授权许可】

CC BY   
© BioMed Central Ltd., part of Springer Nature 2023

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