Role of NRF2 in MiR-181c/AMP-Activated Protein Kinase Signaling in Cancer

Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that regulates an array of antioxidant genes in the oxidative stress defense system. AMP-activated protein kinase (AMPK) is a crucial sensor of energy status and regulates cellular responses to metabolic stress. Cancer cells, which are highly proliferative, should acquire alteration of metabolism to adapt stressful and dynamic microenvironment. Here, we demonstrated that NRF2 activity affected AMPK pathway in cancer cells. Silencing NRF2 in human colorectal adenocarcinoma HT29 cells lowered ATP levels, which induced AMPK activation and subsequent metabolic adaptation signaling including the inhibition of fatty acid and sterol biosynthesis enzymes. As underlying mechanism, increased miR-181c in NRF2-knockdown cancer cells (shNRF2-HT29) was associated with regulation of AMPK signaling. The introduction of miR-181c mimic into control HT29 cells (scHT29) increased phosphorylation of AMPKα and acetyl CoA carboxylase (ACC). Conversely, transfection of miR-181c inhibitor in shNRF2-HT29 cells reduced AMPKα and ACC phosphorylation. Notably, these metabolic signaling changes led to the sensitization of NRF2 -silenced cancer cells to low glucose- and AMPK inhibitor-induced growth suppression. In addition, mouse tumor xenografts from NRF2 -knockdown HT29 showed the growth retardation along with AMPK-driven metabolic gene alterations, which therefore increased the sensitivity to AMPK inhibitor-mediated tumor growth inhibition. All together, these results showed the adaptive activation of AMPK by NRF2 silencing in cancer.