BRAF inhibitor resistance enhances vulnerability to arginine deprivation in melanoma.
BRAF inhibitor resistance enhances vulnerability to arginine deprivation in melanoma.
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DOI：
10.18632/oncotarget.6882
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发表时间：
2016-04-05
期刊：
影响因子：
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通讯作者：
Savaraj N
中科院分区：
文献类型：
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作者：
Li YY;Wu C;Chen SM;Shah SS;Wangpaichitr M;Feun LG;Kuo MT;Suarez M;Prince J;Savaraj N
BRAF抑制剂（BRAFi）已用于治疗携带V600 E突变的黑素瘤。尽管初始响应率很高，但对BRAFi的抵制是不可避免的。在这里，我们证明了BRAFi耐药（BR）黑色素瘤由于不能启动精氨酸琥珀酸合成酶（ASS 1，精氨酸合成的关键酶）的重新表达以及无效的自噬而易受精氨酸剥夺的影响。已知自噬和ASS 1再表达可保护黑色素瘤细胞在精氨酸剥夺后免于细胞死亡。当黑色素瘤细胞通过与BRAFi长期体外孵育变成BR细胞时，c-Myc介导的ASS 1再表达和自噬相关蛋白（AMPK-α1和Atg 5）的水平减弱。此外，我们的研究揭示了去泛素化酶USP 28的下调，这导致通过泛素-蛋白酶体机制更活跃的c-Myc降解是BR细胞中精氨酸剥夺后不能重新表达ASS 1的主要机制。BR细胞中USP 28的过表达增强了c-Myc的表达，因此增加了精氨酸剥夺后的ASS 1转录，从而导致细胞存活。另一方面，Atg 5或AMPK-α1在BR细胞中的过表达可以将精氨酸剥夺诱导的凋亡重定向为自噬。异种移植模型也证实了BR肿瘤具有较低的ASS 1表达，并且对精氨酸剥夺过敏。BRAFi抗性中的这些生物化学变化使得它们易受精氨酸剥夺的影响，可以用于BR黑色素瘤患者的未来治疗。
BRAF inhibitor (BRAFi) has been used for treatment of melanomas harboring V600E mutation. Despite a high initial response rate, resistance to BRAFi is inevitable. Here, we demonstrate that BRAFi-resistant (BR) melanomas are susceptible to arginine deprivation due to inability to initiate re-expression of argininosuccinate synthetase (ASS1, a key enzyme for arginine synthesis) as well as ineffective autophagy. Autophagy and ASS1 re-expression are known to protect melanoma cells from cell death upon arginine deprivation. When melanoma cells become BR cells by long-term in vitro incubation with BRAFi, c-Myc-mediated ASS1 re-expression and the levels of autophagy-associated proteins (AMPK-α1 and Atg5) are attenuated. Furthermore, our study uncovers that downregulation of deubiquitinase USP28 which results in more active c-Myc degradation via ubiquitin-proteasome machinery is the primary mechanism for inability to re-express ASS1 upon arginine deprivation in BR cells. Overexpression of USP28 in BR cells enhances c-Myc expression and hence increases ASS1 transcription upon arginine deprivation, and consequently leads to cell survival. On the other hand, overexpression of Atg5 or AMPK-α1 in BR cells can redirect arginine deprivation-induced apoptosis toward autophagy. The xenograft models also confirm that BR tumors possess lower expression of ASS1 and are hypersensitive to arginine deprivation. These biochemical changes in BRAFi resistance which make them vulnerable to arginine deprivation can be exploited for the future treatment of BR melanoma patients.