当前位置： SCI文献检索 > Redox Biology期刊下所有文献 > Impairment of HIF-1α-mediated metabolic adaption by NRF2-silencing in breast cancer cells.

Impairment of HIF-1α-mediated metabolic adaption by NRF2-silencing in breast cancer cells.

Abstract：

:Hypoxia, a common element in the tumor environment, leads to Hypoxia-Inducible Factor-1α (HIF-1α) stabilization to modulate cellular metabolism as an adaptive response. In a previous study, we showed that inhibition of the nuclear factor erythroid 2-like-2 (NFE2L2; NRF2), a master regulator of many genes coping with electrophilic and oxidative stress, elevated the level of miR-181c and induced mitochondrial dysfunction in colon cancer cells. In this study, we demonstrate that NRF2-silencing hindered HIF-1α accumulation in hypoxic breast cancer cells and subsequently suppressed hypoxia-inducible expression of glycolysis-associated glucose transporter-1, hexokinase-2, pyruvate dehydrogenase kinase-1, and lactate dehydrogenase A. HIF-1α dysregulation in NRF2-silenced cancer cells was associated with miR-181c elevation. Overexpression of miR-181c in breast cancer cells blocked HIF-1α accumulation and diminished hypoxia-inducible levels of glycolysis enzymes, whereas the inhibition of miR-181c in NRF2-silenced cells restored HIF-1α accumulation. In a subsequent metabolomic analysis, hypoxic incubation increased the levels of metabolites involved in glycolysis and activated the pentose phosphate pathway (PPP) in control cells. However, these elevations were less pronounced in NRF2-silenced cells. In particular, hypoxic incubation increased the levels of amino acids, which implies a shift to catabolic metabolism, and the increased levels were higher in control cells than in NRF2-silenced cells. Concurrently, hypoxia activated BCL2 interacting protein 3 (BNIP3)-mediated autophagy in the control cells and miR-181c was found to be involved in this autophagy activation. Taken together, these results show that hypoxia-induced metabolic changes to glycolysis, the PPP, and autophagy are inhibited by NRF2-silencing through miR-181c-mediated HIF-1α dysregulation. Therefore, targeting NRF2/miR-181c could be an effective strategy to counteract HIF-1α-orchestrated metabolic adaptation of hypoxic cancer cells.

journal_name

Redox Biol

journal_title

Redox biology

authors

Lee S,Hallis SP,Jung KA,Ryu D,Kwak MK

doi

10.1016/j.redox.2019.101210

subject

Has Abstract

pub_date

2019-06-01 00:00:00

pages

101210

issn

2213-2317

pii

S2213-2317(19)30050-3

journal_volume

pub_type

杂志文章

在线工具

Impairment of HIF-1α-mediated metabolic adaption by NRF2-silencing in breast cancer cells.