Kyeong-Ah Jung1, Sujin Lee1, Mi-Kyoung Kwak1,2. 1. 1 Department of Pharmacy, Graduate School of The Catholic University of Korea , Bucheon, Gyeonggi-do, Republic of Korea. 2. 2 College of Pharmacy, The Catholic University of Korea , Bucheon, Gyeonggi-do, Republic of Korea.
Abstract
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-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. 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 AMPKα as an adaptive link in cancers. CONCLUSION: 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.
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 humancolon 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, mousetumor 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. 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 AMPKα as an adaptive link in cancers. CONCLUSION: 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.
Entities:
Keywords:
AMP-activated protein kinase; NFE2L2/NRF2; electron transport chain; miR-181c; mitochondria-encoded cytochrome c oxidase subunit-1
Authors: Hemanth N Banavath; Barbara Roman; Nathan Mackowski; Debjit Biswas; Junaid Afzal; Yohei Nomura; Soroosh Solhjoo; Brian O'Rourke; Mark Kohr; Elizabeth Murphy; Charles Steenbergen; Samarjit Das Journal: J Am Heart Assoc Date: 2019-12-05 Impact factor: 5.501