Degradation of AMPK-α1 sensitizes BRAF inhibitor-resistant melanoma cells to arginine deprivation.
Degradation of AMPK-α1 sensitizes BRAF inhibitor-resistant melanoma cells to arginine deprivation.
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DOI：
10.1002/1878-0261.12151
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发表时间：
2017-12
影响因子：
6.6
通讯作者：
Savaraj N
中科院分区：
文献类型：
--
作者：
Li YY;Wu C;Shah SS;Chen SM;Wangpaichitr M;Kuo MT;Feun LG;Han X;Suarez M;Prince J;Savaraj N
已知含有BRAF突变（V600E）的黑色素瘤在使用BRAF抑制剂（BRAFi）治疗后经常复发，尽管初始反应率很高。我们之前的研究发现，BRAFi抗性黑色素瘤（BR）细胞易受精氨酸剥夺的影响。有报道称naïve黑色素瘤细胞经历自噬并重新表达精氨酸琥珀酸合成酶1 (ASS1)，使其在遭遇精氨酸剥夺时能够合成精氨酸以维持生存。在BR细胞中取消这两个因素会导致对精氨酸剥夺的敏感性。在这篇报道中，我们进一步证明了AMPK‐α1在BR细胞中的下调是导致自噬损伤的一个主要因素，自噬体的形成减少证明了这一点。这些BR细胞还表现出从葡萄糖依赖到精氨酸依赖的代谢转变，这是由GLUT1（葡萄糖转运蛋白）和己糖激酶II （HKII）的表达减少以及葡萄糖摄取减少和精氨酸转运蛋白CAT‐2的高水平表达支持的。此外，沉默CAT‐2表达也明显减弱了BR细胞的增殖。值得注意的是，当naïve黑色素瘤细胞通过长期暴露于BRAFi而变成BR细胞时，AMPK - α1通过泛素-蛋白酶体系统（UPS）逐步降解。我们发现一种新的E3连接酶RING finger 44 （RNF44）负责促进BR细胞中AMPK‐α1的降解。RNF44在BR细胞中的表达上调是由ERK/AKT过度激活引发的转录因子CREB引起的。在BR和BRAFi/MEK抑制剂（MEKi）耐药（BMR）黑色素瘤患者的BR异种移植物和黑色素瘤样本中出现了高水平的RNF44，对应于低水平的AMPK α1。与BR细胞相似，BMR细胞对精氨酸剥夺也很敏感。我们的研究为BRAFi或BRAFi/MEKi耐药驱动AMPK‐α1蛋白酶体降解的机制提供了新的见解，从而调节黑色素瘤细胞的自噬和代谢重编程。
Melanomas harboring BRAF mutation (V600E) are known to recur frequently following treatment with BRAF inhibitors (BRAFi) despite a high initial response rate. Our previous study has uncovered that BRAFi‐resistant melanoma (BR) cells are vulnerable to arginine deprivation. It has been reported that naïve melanoma cells undergo autophagy and re‐express argininosuccinate synthetase 1 (ASS1) to enable them to synthesize arginine for survival when encountering arginine deprivation. Abolishing these two factors in BR cells confers sensitivity to arginine deprivation. In this report, we further demonstrated that downregulation of AMPK‐α1 in BR cells is a major factor contributing to impairment of autophagy as evidenced by decreased autophagosome formation. These BR cells also showed a metabolic shift from glucose to arginine dependence, which was supported by decreased expressions of GLUT1 (glucose transporter) and hexokinase II (HKII) coupled with less glucose uptake but high levels of arginine transporter CAT‐2 expression. Furthermore, silencing CAT‐2 expression also distinctly attenuated BR cell proliferation. Notably, when naïve melanoma cells became BR cells by long‐term exposure to BRAFi, a stepwise degradation of AMPK‐α1 was initiated via ubiquitin‐proteasome system (UPS). We discovered that a novel E3 ligase, RING finger 44 (RNF44), is responsible for promoting AMPK‐α1 degradation in BR cells. RNF44 expression in BR cells was upregulated by transcription factor CREB triggered by hyperactivation of ERK/AKT. High levels of RNF44 corresponding to low levels of AMPK‐α1 appeared in BR xenografts and melanoma tumor samples from BR and BRAFi/MEK inhibitor (MEKi)‐resistant (BMR) melanoma patients. Similar to BR cells, BMR cells were also sensitive to arginine deprivation. Our study provides a novel insight into the mechanism whereby BRAFi or BRAFi/MEKi resistance drives proteasomal degradation of AMPK‐α1 and consequently regulates autophagy and metabolic reprogramming in melanoma cells.
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