Activation of Ras/PI3K/ERK pathway induces c-Myc stabilization to upregulate argininosuccinate synthetase, leading to arginine deiminase resistance in melanoma cells.
Activation of Ras/PI3K/ERK pathway induces c-Myc stabilization to upregulate argininosuccinate synthetase, leading to arginine deiminase resistance in melanoma cells.
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DOI：
10.1158/0008-5472.can-11-3605
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发表时间：
2012-05-15
期刊：
影响因子：
11.2
通讯作者：
Kuo MT
中科院分区：
文献类型：
--
作者：
Tsai WB;Aiba I;Long Y;Lin HK;Feun L;Savaraj N;Kuo MT
不表达精氨酸生物合成的限速酶--精氨酸琥珀酸合成酶（AS）的黑素瘤和其他癌症对聚乙二醇化精氨酸脱亚胺酶（ADI-PEG 20）的精氨酸消耗敏感。然而，由于AS上调，ADI抗性最终在肿瘤中发展。虽然已经表明AS上调涉及c-Myc，但其潜在机制仍然未知。我们发现ADI-PEG 20激活Ras信号传导和效应ERK和PI 3 K/AKT/GSK-3β激酶级联，通过减弱其泛素介导的蛋白降解机制导致c-Myc的磷酸化和稳定化。使用PI 3 K/AKT抑制剂抑制诱导的细胞信号传导途径抑制了c-Myc诱导并增强了ADI介导的细胞杀伤。值得注意的是，在AS阴性黑色素瘤的动物模型中，与单独使用任一种药物相比，使用PI 3 K抑制剂加ADI-PEG 20的联合治疗产生了相加的抗肿瘤作用。综上所述，我们的研究结果为精氨酸剥夺代谢和ADI抗性提供了机制性见解，并且它们说明了Ras/ERK和PI 3 K/AKT信号通路的组合抑制剂如何改善ADI-PEG 20抗癌反应。
Melanomas and other cancers that do not express argininosuccinate synthetase (AS), the rate-limiting enzyme for arginine biosynthesis, are sensitive to arginine depletion with pegylated arginine deiminase (ADI-PEG20). However, ADI resistance eventually develops in tumors due to AS upregulation. Although it has been shown that AS upregulation involves c-Myc, the underlying mechanisms remain unknown. Here we show that ADI-PEG20 activates Ras signaling and the effector ERK and PI3K/AKT/GSK-3β kinase cascades, resulting in phosphorylation and stabilization of c-Myc by attenuation of its ubiquitin-mediated protein degradation mechanism. Inhibition of the induced cell signaling pathways using PI3K/AKT inhibitors suppressed c-Myc induction and enhanced ADI-mediated cell killing. Notably, in an animal model of AS-negative melanoma, combination therapy using a PI3K inhibitor plus ADI-PEG20 yielded additive anti-tumor effects as compared with either agent alone. Taken together, our findings offer mechanistic insight into arginine deprivation metabolism and ADI resistance, and they illustrate how combining inhibitors of the Ras/ERK and PI3K/AKT signaling pathways may improve ADI-PEG20 anti-cancer responses.