title: NFE2L2/NRF2 Activity Is Linked to Mitochondria and AMP-Activated Protein Kinase Signaling in Cancers Through miR-181c/Mitochondria-Encoded Cytochrome c Oxidase Regulation.
abstract: OBJECTIVE
  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-κB 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-α (AMPKα) activation and subsequent metabolic adaptation signaling, including the inhibition of fatty acid and sterol biosynthesis enzymes. As supportive evidence of AMPKα-driven adaption, NFE2L2/NRF2-silenced cells were more vulnerable to AMPKα inhibition-induced growth suppression. Similarly, mouse tumor xenografts derived from NFE2L2/NRF2-silenced HT29 exhibited MT-CO1 reduction and AMPKα activation, thereby increasing responsiveness to the AMPK inhibitor treatment. The association of NFE2L2/NRF2 with MT-CO1 and AMPKα was confirmed in breast cancer cells.
  
  
  METHODS
  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 AMPKα as an adaptive link in cancers.
  
  
  CONCLUSIONS
  Therefore, it may be an effective strategy to inhibit both NFE2L2/NRF2 and AMPKα signaling to overcome adaptive behaviors of cancer. Antioxid. Redox Signal. 27, 945-961.
authors.affiliation: 1 Department of Pharmacy, Graduate School of The Catholic University of Korea , Bucheon, Gyeonggi-do, Republic of Korea.
authors.forename: Kyeong-Ah
authors.initials: KA
authors.lastname: Jung
authors.affiliation: 1 Department of Pharmacy, Graduate School of The Catholic University of Korea , Bucheon, Gyeonggi-do, Republic of Korea.
authors.forename: Sujin
authors.initials: S
authors.lastname: Lee
authors.affiliation: 1 Department of Pharmacy, Graduate School of The Catholic University of Korea , Bucheon, Gyeonggi-do, Republic of Korea.|2 College of Pharmacy, The Catholic University of Korea , Bucheon, Gyeonggi-do, Republic of Korea.
authors.forename: Mi-Kyoung
authors.initials: MK
authors.lastname: Kwak
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D008928:Mitochondria / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009368:Neoplasm Transplantation; D015398:Signal Transduction
chemical_list: C540193:MIrn181 microRNA, human; D035683:MicroRNAs; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D003576:Electron Transport Complex IV; C581860:cytochrome c oxidase subunit I, human; D055372:AMP-Activated Protein Kinases
keywords: AMP-activated protein kinase; NFE2L2/NRF2; electron transport chain; miR-181c; mitochondria-encoded cytochrome c oxidase subunit-1