Targeting metabolic activity in high-risk neuroblastoma through Monocarboxylate Transporter 1 (MCT1) inhibition.
Targeting metabolic activity in high-risk neuroblastoma through Monocarboxylate Transporter 1 (MCT1) inhibition.
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DOI：
10.1038/s41388-020-1235-2
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发表时间：
2020-04
期刊：
影响因子：
8
通讯作者：
Yu DMT
中科院分区：
文献类型：
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作者：
Khan A;Valli E;Lam H;Scott DA;Murray J;Hanssen KM;Eden G;Gamble LD;Pandher R;Flemming CL;Allan S;Osterman AL;Haber M;Norris MD;Fletcher JI;Yu DMT
MYCN癌基因扩增发生在约25%的原发性神经母细胞瘤中，是该疾病预后不良的唯一最有力的生物学标志物。MYCN转录调节一系列对癌症重要的生物过程，包括细胞代谢。mycn调控的代谢基因SLC16A1编码乳酸转运蛋白单羧酸转运蛋白1 (MCT1)，是一个潜在的治疗靶点。用MCT1抑制剂SR13800治疗神经母细胞瘤细胞增加细胞内乳酸水平，破坏烟酰胺腺嘌呤二核苷酸（NADH/NAD+）比例，降低细胞内谷胱甘肽水平。MCT1抑制剂治疗后，13c -葡萄糖和13c -谷氨酰胺代谢物示踪显示三羧酸（TCA）循环中间体数量增加，耗氧量增加。在细胞培养条件下，MCT1抑制与长春新碱具有高度协同作用，但这种组合对小鼠神经母细胞瘤异种移植物无效。治疗后的异种移植物肿瘤增加了MCT1同系物MCT4/SLC16A的表达，这是一种已知的MCT1抑制的抗性因子。我们发现，在荧光素酶报告基因检测中，MCT4受到MYCN的负调控，并且在缺氧条件下和缺氧诱导因子（HIF1）诱导下，MCT4在神经母细胞瘤细胞中的表达增加，这表明MCT4可能参与了缺氧神经母细胞瘤肿瘤对MCT1抑制剂治疗的抵抗。神经母细胞瘤细胞与MCT1和LDHA（负责乳酸生成的酶）抑制剂共同治疗，导致细胞内丙酮酸大量增加，并在降低神经母细胞瘤细胞活力方面具有高度协同作用。这些结果强调了在神经母细胞瘤中靶向MCT1的潜力，以及涉及破坏丙酮酸稳态的策略，并指出了可能的耐药机制。
Amplification of the MYCN oncogene occurs in approximately 25% of primary neuroblastomas and is the single most powerful biological marker of poor prognosis in this disease. MYCN transcriptionally regulates a range of biological processes important for cancer, including cell metabolism. The MYCN-regulated metabolic gene SLC16A1, encoding the lactate transporter monocarboxylate transporter 1 (MCT1), is a potential therapeutic target. Treatment of neuroblastoma cells with the MCT1 inhibitor SR13800 increased intracellular lactate levels, disrupted the nicotinamide adenine dinucleotide (NADH/NAD+) ratio and decreased intracellular glutathione levels. Metabolite tracing with 13C-glucose and 13C-glutamine following MCT1 inhibitor treatment revealed increased quantities of tricarboxylic acid (TCA) cycle intermediates and increased oxygen consumption rate. MCT1 inhibition was highly synergistic with vincristine under cell culture conditions, but this combination was ineffective against neuroblastoma xenografts in mice. Post-treatment xenograft tumors had increased expression of the MCT1 homolog MCT4/SLC16A, a known resistance factor to MCT1 inhibition. We found that MCT4 was negatively regulated by MYCN in luciferase reporter assays and its expression in neuroblastoma cells was increased under hypoxic conditions and following hypoxia-inducible factor (HIF1) induction, suggesting that MCT4 may contribute to resistance to MCT1 inhibitor treatment in hypoxic neuroblastoma tumors. Co-treatment of neuroblastoma cells with inhibitors of MCT1 and LDHA, the enzyme responsible for lactate production, resulted in a large increase in intracellular pyruvate and was highly synergistic in decreasing neuroblastoma cell viability. These results highlight the potential of targeting MCT1 in neuroblastoma in conjunction with strategies that involve disruption of pyruvate homeostasis and indicate possible resistance mechanisms.
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