Gas6/Axl is the sensor of arginine-auxotrophic response in targeted chemotherapy with arginine-depleting agents.
Gas6/Axl is the sensor of arginine-auxotrophic response in targeted chemotherapy with arginine-depleting agents.
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DOI：
10.1038/onc.2015.237
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发表时间：
2016-03-31
期刊：
影响因子：
8
通讯作者：
Kuo MT
中科院分区：
文献类型：
--
作者：
Tsai WB;Long Y;Park JR;Chang JT;Liu H;Rodriguez-Canales J;Savaraj N;Feun LG;Davies MA;Wistuba II;Kuo MT
许多人类恶性肿瘤缺乏精氨酸(Arg)的从头合成，因为关键酶精氨酸琥珀酸合成酶1(ASS1)是沉默的。这些肿瘤获得异位Arg以求生存，而通过耗尽Arg的重组酶ADI-PEG20来耗尽这一来源会导致细胞死亡。这些肿瘤中Arg营养缺乏症的潜在机制以及它们如何应对Arg营养缺乏症的压力还知之甚少。在这里，我们报告了Arg营养缺乏症反应的一个即刻早期事件，涉及ROS介导的Gas6的分泌，Gas6与其受体Axl相互作用，激活下游的RAS/PI3K/Akt生长信号，通过蛋白质稳定导致c-Myc的积累。Arg营养缺乏症还在转录上上调c-Myc的表达，而c-Myc的表达反过来又促进Ax1的表达。C-Myc是ASS1的正调控因子，但升高的ASS1反馈抑制c-Myc和Ax1。我们的结果揭示了Arg营养缺乏症反应中的多个相互调节通路，包括Ax1、c-Myc、ASS1，它们调节Arg的动态平衡和ADI-PEG20敏感性。这些途径为提高精氨酸缺乏性肿瘤的治疗效果提供了潜在的靶点。
Many human malignancies lack de novo biosynthesis of arginine (Arg) because the key enzyme argininosuccinate synthetase 1 (ASS1) is silenced. These tumors acquire ectopic Arg for survival, and depleting this source by Arg-depleting recombinant enzyme ADI-PEG20 results in cell death. Mechanisms underlying Arg auxotrophy in these tumors and how they respond to Arg-auxotrophic stress are poorly understood. Here, we report that an immediate early event of Arg-auxotrophic response involves ROS-mediated secretion of Gas6 which interacts with its receptor Axl and activates the downstream Ras/PI3K/Akt growth signal leading to accumulation of c-Myc by protein stabilization. Arg-auxotrophic challenge also transcriptionally upregulates c-Myc expression which feedbacks to enhance Axl expression. c-Myc is a positive regulator of ASS1, but elevated ASS1 feedbacks to suppress c-Myc and Axl. Our results revealed multiple inter-regulatory pathways in Arg-auxotrophic response consisting of Axl, c-Myc, ASS1 that regulate Arg homeostasis and ADI-PEG20 sensitivity. These pathways provide potential targets for improving the efficacy of treating Arg-auxotrophic tumors using Arg deprivation strategies.