Deferoxamine suppresses esophageal squamous cell carcinoma cell growth far via ERK1/2 mediated mitochondrial dysfunction
Deferoxamine suppresses esophageal squamous cell carcinoma cell growth far via ERK1/2 mediated mitochondrial dysfunction
复制标题
去铁胺通过 ERK1/2 介导的线粒体功能障碍抑制食管鳞状细胞癌细胞生长。
DOI：
10.1016/j.canlet.2018.06.012
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发表时间：
2018-01-01
期刊：
影响因子：
9.7
通讯作者：
Lu, Bin
中科院分区：
文献类型：
--
作者：
Lan, Linhua;Wei, Wei;Lu, Bin
去铁胺（DFO）被发现可以调节多种参与乳腺癌、肝细胞癌、肺癌和膀胱癌生长的细胞通路。然而，DFO对食管鳞状细胞癌（ESCC）的影响尚不清楚。在这里，我们报道了dfo处理的ESCC细胞表现出很强的抗肿瘤特性，如抑制细胞增殖，诱导细胞周期阻滞和促进细胞凋亡。在机制上，DFO显著激活ERK1/2信号，这是活性氧（ROS）依赖的。ERK1/2激活抑制ESCC细胞的线粒体呼吸和有氧糖酵解，导致ATP和关键前体代谢产物的产生减少。活性氧清除剂n -乙酰-t-半胱氨酸（NAC）和ERK1/2抑制剂SCH7 72984在功能上挽救了细胞的增殖。此外，我们的数据显示，激活的ERK1/2部分易位到线粒体，这表明dfo激活的ERK1/2可能通过抑制线粒体呼吸来抑制肿瘤的形成。此外，DFO引起的c-Myc表达降低导致细胞迁移受到抑制。综上所述，我们的研究表明，DFO激活ERK1/2，下调c-Myc，扰乱线粒体稳态，促进细胞凋亡，从而导致DFO在ESCC中具有新的抗肿瘤活性。
Deferoxamine (DFO) was found to modulate multiple cellular pathways involved in the growth of breast cancer, hepatocellular carcinoma, lung cancer and bladder cancer. However, the effect of DFO on esophageal squamous cell carcinoma (ESCC) remains unclear. Here, we report that DFO-treated ESCC cells show strong anti-tumorigenic properties, such as inhibition of cell proliferation, induction of cell cycle arrest, and promotion of apoptosis. Mechanistically, DFO significantly activated ERK1/2 signaling, which is reactive oxygen species (ROS)dependent. ERK1/2 activation suppressed mitochondrial respiration and aerobic glycolysis in ESCC cells, resulting in reduced production of ATP and key precursor metabolites. Cell proliferation was functionally rescued by the ROS scavenger N-acetyl-t-cysteine (NAC) and the ERK1/2 inhibitor SCH7 72984. Additionally, our data showed that activated ERK1/2 was partially translocated to the mitochondria, which indicated that DFO-activated ERK1/2 may suppress tumor formation through inhibition of mitochondrial respiration. Moreover, the decreased c-Myc expression caused by DFO resulted in the inhibition of cell migration. Taken together, our study demonstrate that DFO activates ERK1/2 and downregulates c-Myc to perturb mitochondrial homeostasis and promote apoptosis, resulting in the novel anti-neoplastic activity of DFO in ESCC.