AMPK promotes survival of c-Myc-positive melanoma cells by suppressing oxidative stress
AMPK promotes survival of c-Myc-positive melanoma cells by suppressing oxidative stress
复制标题
DOI：
10.15252/embj.201797673
复制
发表时间：
2018-03-01
期刊：
影响因子：
11.4
通讯作者：
Radtke, Freddy
中科院分区：
文献类型：
--
作者：
Kfoury, Alain;Armaro, Marzia;Radtke, Freddy
虽然c-Myc对黑素细胞发育至关重要，但其在皮肤黑色素瘤（最具侵袭性的皮肤癌）中的作用仅部分了解。在这里，我们使用Nras（Q61 K）INK 4a（-/-）小鼠黑色素瘤模型来显示c-Myc对于肿瘤起始、维持和转移是必需的。表达c-Myc的黑色素瘤细胞优先出现在转移部位，与肿瘤侵袭性增加和高肿瘤起始潜力相关。去除c-Myc引起原代鼠和人黑色素瘤细胞凋亡。从机制上讲，c-Myc阳性黑色素瘤细胞激活并依赖于代谢能量传感器AMP活化蛋白激酶（AMPK），AMPK是一种代谢检查点激酶，在应激条件下的能量和氧化还原稳态中发挥重要作用。AMPK通路抑制引起表达c-Myc的黑色素瘤细胞凋亡，而AMPK激活通过抑制氧化应激保护c-Myc缺失的黑色素瘤细胞免于细胞死亡。此外，对早期人类黑色素瘤样本的TCGA数据库分析揭示了C-MYC与患者生存率之间的负相关性，表明C-MYC表达水平可以作为早期疾病的预后标志物。
Although c-Myc is essential for melanocyte development, its role in cutaneous melanoma, the most aggressive skin cancer, is only partly understood. Here we used the Nras(Q61K)INK4a(-/-) mouse melanoma model to show that c-Myc is essential for tumor initiation, maintenance, and metastasis. c-Myc-expressing melanoma cells were preferentially found at metastatic sites, correlated with increased tumor aggressiveness and high tumor initiation potential. Abrogation of c-Myc caused apoptosis in primary murine and human melanoma cells. Mechanistically, c-Myc-positive melanoma cells activated and became dependent on the metabolic energy sensor AMP-activated protein kinase (AMPK), a metabolic checkpoint kinase that plays an important role in energy and redox homeostasis under stress conditions. AMPK pathway inhibition caused apoptosis of c-Myc-expressing melanoma cells, while AMPK activation protected against cell death of c-Myc-depleted melanoma cells through suppression of oxidative stress. Furthermore, TCGA database analysis of early-stage human melanoma samples revealed an inverse correlation between C-MYC and patient survival, suggesting that C-MYC expression levels could serve as a prognostic marker for early-stage disease.