The nuclear factor erythroid 2-like-2 (NFE2L2/NRF2) pathway contributes to the environmental resistance of cancers by enhancing the antioxidant capacity. Hypoxia, a common element in the tumor environment, leads to hypoxia-inducible factor-1α (HIF-1α) stabilization to induce the adaptive response to hypoxic condition, including metabolic reprogramming and blood vessel formation. Our global miRNA expression analysis of HT29 and HCT116 human colon cancer cells identified that NRF2 silencing upregulated miR-181c, 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. Therefore, NRF2-silenced cancer cells exhibited the decreases in the mitochondrial membrane potential, oxygen consumption rate, and cellular ATP contents. Notably, as a result of low oxygen consumption rate, NRF2-inhibited cancer cells failed to accumulate HIF-1a protein under hypoxic conditions. This phenomenon led to differential responses of NRF2-inhibted cancer cells to hypoxic condition when compared to control cells. First, stable knockdown of NRF2 in human colon cancer cells suppressed tumor growth in mouse xenograft settings with a concomitant reduction in blood vessel formation and vascular endothelial growth factor expression. Second, NRF2-silencing in breast cancer cells inhibited metabolic adaptation upon hypoxia, and hypoxic-inducible levels of metabolites involved in glycolysis and pentose phosphate pathway were reduced. Collectively, targeting NRF2/miR-181c could be an effective strategy to counteract HIF-1α-orchestrated adaptation of cancer cells to hypoxic microenvironment.

Citation Format: Mi-Kyoung Kwak, Sujin Lee, Steffanus Pranoto Hallis. Inhibitory role of NFE2L2/NRF2-silencing in hypoxia-induced metabolic adaptation of cancer cells [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B079. doi:10.1158/1535-7163.TARG-19-B079