In vivo characterization of glutamine metabolism identifies therapeutic targets in clear cell renal cell carcinoma.
In vivo characterization of glutamine metabolism identifies therapeutic targets in clear cell renal cell carcinoma.
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DOI：
10.1126/sciadv.abp8293
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发表时间：
2022-12-16
期刊：
影响因子：
13.6
通讯作者：
中科院分区：
文献类型：
--
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靶向代谢脆弱性已被提出作为肾细胞癌（RCC）的治疗策略。在这里，我们分析了来自不同亚型RCC的患者来源的异种移植物（肿瘤移植物）的代谢。VHL突变型透明细胞RCC（ccRCC）的肿瘤移植物保留了人ccRCC的代谢特征，并参与氧化和还原谷氨酰胺代谢。异柠檬酸脱氢酶-1或异柠檬酸脱氢酶-2的基因沉默损害了体内三羧酸（TCA）循环中间体的还原标记，并抑制了肿瘤移植物衍生细胞产生的肿瘤的生长。谷氨酰胺酶抑制剂减少了谷氨酰胺对TCA循环的贡献，并导致肿瘤移植物生长的适度抑制。输注[酰胺-15 N]谷氨酰胺显示在转氨酶抑制期间持续的酰胺转移酶活性，并且用酰胺转移酶抑制剂JHU-083阻断这些活性也降低了免疫功能低下和免疫活性小鼠中的肿瘤生长。我们得出结论，ccRCC肿瘤移植物通过多种途径分解代谢谷氨酰胺，这也许解释了为什么通过抑制谷氨酰胺酶在患者中实现治疗反应具有挑战性。谷氨酰胺促进透明细胞肾细胞癌中的TCA循环和酰胺转移酶途径。
Targeting metabolic vulnerabilities has been proposed as a therapeutic strategy in renal cell carcinoma (RCC). Here, we analyzed the metabolism of patient-derived xenografts (tumorgrafts) from diverse subtypes of RCC. Tumorgrafts from VHL-mutant clear cell RCC (ccRCC) retained metabolic features of human ccRCC and engaged in oxidative and reductive glutamine metabolism. Genetic silencing of isocitrate dehydrogenase-1 or isocitrate dehydrogenase-2 impaired reductive labeling of tricarboxylic acid (TCA) cycle intermediates in vivo and suppressed growth of tumors generated from tumorgraft-derived cells. Glutaminase inhibition reduced the contribution of glutamine to the TCA cycle and resulted in modest suppression of tumorgraft growth. Infusions with [amide-15N]glutamine revealed persistent amidotransferase activity during glutaminase inhibition, and blocking these activities with the amidotransferase inhibitor JHU-083 also reduced tumor growth in both immunocompromised and immunocompetent mice. We conclude that ccRCC tumorgrafts catabolize glutamine via multiple pathways, perhaps explaining why it has been challenging to achieve therapeutic responses in patients by inhibiting glutaminase. Glutamine fuels the TCA cycle and amidotransferase pathways in clear cell renal cell carcinoma.
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影响因子：
64.8
作者：
Jiang L;Shestov AA;Swain P;Yang C;Parker SJ;Wang QA;Terada LS;Adams ND;McCabe MT;Pietrak B;Schmidt S;Metallo CM;Dranka BP;Schwartz B;DeBerardinis RJ
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