ATF4 and N-Myc coordinate glutamine metabolism in MYCN-amplified neuroblastoma cells through ASCT2 activation
ATF4 and N-Myc coordinate glutamine metabolism in MYCN-amplified neuroblastoma cells through ASCT2 activation
复制标题
ATF4 和 N-Myc 通过 ASCT2 激活协调 MYCN 扩增的神经母细胞瘤细胞中的谷氨酰胺代谢
DOI：
10.1002/path.4429
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发表时间：
2015-01-01
影响因子：
7.3
通讯作者：
Qing, Guoliang
中科院分区：
文献类型：
--
作者：
Ren, Ping;Yue, Ming;Qing, Guoliang
人神经母细胞瘤中MYCN基因的扩增预示着不良预后和对治疗的抵抗。我们以前表明，MYCN扩增的神经母细胞瘤细胞不断需要大量的谷氨酰胺，以支持其有增无减的增长。然而，在MYCN扩增的神经母细胞瘤细胞中捕获谷氨酰胺的转运蛋白的身份和调节以及转运蛋白在神经母细胞瘤诊断中的临床意义在很大程度上仍然未知。在这里，我们进行了系统性谷氨酰胺流入分析，并确定MYCN扩增的神经母细胞瘤细胞主要依赖于ASCT 2（溶质载体家族1成员5，SLC 1A 5）的激活，以维持TCA循环回补所必需的足够水平的谷氨酰胺。因此，ASCT 2消耗深刻地抑制了多巴胺的分解，伴随着体外细胞增殖和活力的显著降低以及体内肿瘤发生的抑制。从机制上讲，我们将ATF 4鉴定为与N-Myc协调直接激活ASCT 2表达的新型调节因子。值得注意的是，与N-Myc和ATF 4的表达相关的ASCT 2表达在高阶段神经母细胞瘤肿瘤样品中与低阶段相比显著升高。更重要的是，ASCT 2高表达与神经母细胞瘤患者的不良预后和生存率显著相关。总的来说，这些发现阐明了一种新的机制，描述了细胞自主损伤（MYCN扩增）和微环境应激（ATF 4诱导）如何协调ASCT 2激活以促进侵袭性神经母细胞瘤进展，并将ASCT 2确立为患者预后和分层的新生物标志物。版权所有（c）2014大不列颠和爱尔兰病理学会。出版社：John Wiley & Sons，Ltd
Amplification of the MYCN gene in human neuroblastoma predicts poor prognosis and resistance to therapy. We previously showed that MYCN-amplified neuroblastoma cells constantly require large amounts of glutamine to support their unabated growth. However, the identity and regulation of the transporter(s) that capture glutamine in MYCN-amplified neuroblastoma cells and the clinical significance of the transporter(s) in neuroblastoma diagnosis remain largely unknown. Here, we performed a systemic glutamine influx analysis and identified that MYCN-amplified neuroblastoma cells predominantly rely on activation of ASCT2 (solute carrier family 1 member 5, SLC1A5) to maintain sufficient levels of glutamine essential for the TCA cycle anaplerosis. Consequently, ASCT2 depletion profoundly inhibited glutaminolysis, concomitant with a substantial decrease in cell proliferation and viability in vitro and inhibition of tumourigenesis in vivo. Mechanistically, we identified ATF4 as a novel regulator which coordinates with N-Myc to directly activate ASCT2 expression. Of note, ASCT2 expression, which correlates with that of N-Myc and ATF4, is markedly elevated in high-stage neuroblastoma tumour samples compared with low-stage ones. More importantly, high ASCT2 expression is significantly associated with poor prognosis and survival of neuroblastoma patients. In aggregate, these findings elucidate a novel mechanism depicting how cell autonomous insults (MYCN amplification) and microenvironmental stresses (ATF4 induction) in concert coordinate ASCT2 activation to promote aggressive neuroblastoma progression, and establish ASCT2 as a novel biomarker in patient prognosis and stratification. Copyright (c) 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd