NDRG2 overexpression suppresses hepatoma cells survival during metabolic stress through disturbing the activation of fatty acid oxidation
NDRG2 overexpression suppresses hepatoma cells survival during metabolic stress through disturbing the activation of fatty acid oxidation
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NDRG2 过表达通过干扰脂肪酸氧化的激活来抑制代谢应激期间肝癌细胞的存活
DOI：
10.1016/j.bbrc.2017.01.018
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发表时间：
2017-02-05
影响因子：
3.1
通讯作者：
Li, Xia
中科院分区：
文献类型：
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作者：
Pan, Tao;Zhang, Mei;Li, Xia
由于营养消耗高和血管化不足，实体瘤在肿瘤发展过程中不断承受代谢应激。癌基因和抑癌基因参与癌细胞的代谢重编程。 N-Myc 下游调节基因 2 (NDRG2) 是最近发现的一种肿瘤抑制基因，但其在癌症代谢中的功能，特别是在代谢应激期间的功能仍不清楚。在这项研究中，我们发现NDRG2过表达在葡萄糖限制下显着降低肝癌细胞增殖并增强细胞凋亡。此外，NDRG2 过表达通过减少细胞内 ATP 和 NADPH 的生成并增加 ROS 水平，加剧了能量失衡和氧化应激。引人注目的是，NDRG2 抑制脂肪酸氧化 (FAO) 的激活，从而在没有葡萄糖的情况下保留 ATP 和 NADPH 的供应。最后，机制研究表明，NDRG2 过表达抑制了肝癌细胞中葡萄糖剥夺诱导的 AMPK/ACC 通路激活，而 AMPK 的组成型活性形式的表达消除了葡萄糖剥夺诱导的 AMPK 激活和细胞凋亡。因此，NDRG2作为AMPK的负调节因子，干扰葡萄糖限制对FAO基因的诱导，导致ATP和NADPH失调，从而降低肝癌细胞对葡萄糖限制的耐受性。 (C) 2017 Elsevier Inc. 保留所有权利。
Because of the high nutrient consumption and inadequate vascularization, solid tumor constantly undergoes metabolic stress during tumor development. Oncogenes and tumor suppressor genes participated in cancer cells' metabolic reprogramming. N-Myc downstream regulated gene 2 (NDRG2) is a recently identified tumor suppressor gene, but its function in cancer metabolism, particularly during metabolic stress, remains unclear. In this study, we found that NDRG2 overexpression significantly reduced hepatoma cell proliferation and enhanced cell apoptosis under glucose limitation. Moreover, NDRG2 overexpression aggravated energy imbalance and oxidative stress by decreasing the intracellular ATP and NADPH generation and increasing ROS levels. Strikingly, NDRG2 inhibited the activation of fatty acid oxidation (FAO), which preserves ATP and NADPH purveyance in the absence of glucose. Finally, mechanistic investigation showed that NDRG2 overexpression suppressed the glucose-deprivation induced AMPK/ACC pathway activation in hepatoma cells, whereas the expression of a constitutively active form of AMPK abrogated glucose-deprivation induced AMPK activation and cell apoptosis. Thus, as a negative regulator of AMPK, NDRG2 disturbs the induction of FAO genes by glucose limitation, leading to dysregulation of ATP and NADPH, and thus reduces the tolerance of hepatoma cells to glucose limitation. (C) 2017 Elsevier Inc. All rights reserved.