NFE2L2/NRF2 Activity Is Linked to Mitochondria and AMP-Activated Protein Kinase Signaling in Cancers Through miR-181c/Mitochondria-Encoded Cytochrome c Oxidase Regulation
NFE2L2/NRF2 Activity Is Linked to Mitochondria and AMP-Activated Protein Kinase Signaling in Cancers Through miR-181c/Mitochondria-Encoded Cytochrome c Oxidase Regulation
复制标题
DOI：
10.1089/ars.2016.6797
复制
发表时间：
2017-11-01
影响因子：
6.6
通讯作者：
Kwak, Mi-Kyoung
中科院分区：
文献类型：
--
作者：
Jung, Kyeong-Ah;Lee, Sujin;Kwak, Mi-Kyoung
目的：核因子（红细胞衍生2）样2（NFE 2L 2; NFE 2L 2/NRF 2）途径通过增强抗氧化能力而有助于癌症的环境抗性。在这里，我们探索了NFE 2L 2/NRF 2和癌症中线粒体功能之间的潜在联系。对HT 29和HCT 116人结肠癌细胞的总体miRNA表达分析表明，NFE 2 L2/NRF 2沉默通过核因子-κ B信号转导上调miR-181 c，这种增加与mRNA编码的细胞色素c氧化酶亚基-1（MT-CO 1）的减少有关，电子传递链（ETC）的复合物IV的催化核心亚基。作为ETC功能障碍的结果，NFE 2L 2/NRF 2沉默的癌细胞表现出线粒体膜电位、耗氧速率和细胞三磷酸腺苷（ATP）含量的降低。值得注意的是，这些变化诱导腺苷一磷酸（AMP）激活的蛋白激酶-α（AMPK α）激活和随后的代谢适应信号传导，包括抑制脂肪酸和甾醇生物合成酶。作为AMPK α驱动适应的支持性证据，NFE 2L 2/NRF 2沉默细胞更容易受到AMPKa抑制诱导的生长抑制。类似地，源自NFE 2L 2/NRF 2沉默的HT 29的小鼠肿瘤异种移植物表现出MT-CO 1减少和AMPKa活化，从而增加对AMPK抑制剂治疗的响应性。在乳腺癌细胞中证实了NFE 2L 2/NRF 2与MT-CO 1和AMPKa的关联。创新：我们通过阐明miR-181 c/MT-CO 1作为潜在分子事件的参与来证明NFE 2L 2/NRF 2在癌症线粒体中的重要性。结论：抑制NFE 2L 2/NRF 2和AMPKa信号通路可能是克服肿瘤适应性行为的有效策略。
Aims: The nuclear factor (erythroid-derived 2)-like 2 (NFE2L2; NFE2L2/NRF2) pathway contributes to the environmental resistance of cancers by enhancing the antioxidant capacity. Here, we explored the potential connection between NFE2L2/NRF2 and mitochondrial function in cancers.Results: Global miRNA expression analysis of HT29 and HCT116 human colon cancer cells identified that NFE2L2/NRF2 silencing upregulated miR-181c through nuclear factor-kappa B signaling, and this increase was associated with the reduction in mitochondria-encoded cytochrome c oxidase subunit-1 (MT-CO1), a catalytic core subunit of the complex IV of the electron transport chain (ETC). As a result of ETC dysfunction, NFE2L2/NRF2-silenced cancer cells exhibited the decreases in the mitochondrial membrane potential, oxygen consumption rate, and cellular adenosine triphosphate (ATP) contents. Notably, these changes induced adenosine monophosphate (AMP)-activated protein kinase-alpha (AMPK alpha) activation and subsequent metabolic adaptation signaling, including the inhibition of fatty acid and sterol biosynthesis enzymes. As supportive evidence of AMPK alpha-driven adaption, NFE2L2/NRF2-silenced cells were more vulnerable to AMPKa inhibition-induced growth suppression. Similarly, mouse tumor xenografts derived from NFE2L2/NRF2-silenced HT29 exhibited MT-CO1 reduction and AMPKa activation, thereby increasing responsiveness to the AMPK inhibitor treatment. The association of NFE2L2/NRF2 with MT-CO1 and AMPKa was confirmed in breast cancer cells.Innovation: We demonstrated the significance of NFE2L2/NRF2 in cancer mitochondria by elucidating the involvement of miR-181c/MT-CO1 as underlying molecular events. We also provide evidence of the crosstalk between NFE2L2/NRF2 and AMPKa as an adaptive link in cancers.Conclusion: Therefore, it may be an effective strategy to inhibit both NFE2L2/NRF2 and AMPKa signaling to overcome adaptive behaviors of cancer.