Hexokinase 2 and nuclear factor erythroid 2–related factor 2 transcriptionally coactivate xanthine oxidoreductase expression in stressed glioma cells

Abstract

A dynamic network of metabolic adaptations, inflammatory responses and redox homeostasis is known to drive tumor progression. A considerable overlap between these processes exists, but several of their key regulators remain unknown. To this end, here we investigated the role of the proinflammatory cytokine IL-1β in connecting these processes in glioma cells. We found that glucose starvation sensitizes glioma cells to IL-1β-induced apoptosis in a manner that depended on reactive oxygen species (ROS).Although IL-1β-induced JNK had no effect on cell viability under glucose deprivation, it mediated nuclear translocation of hexokinase 2 (HK2). This event was accompanied by increases in the levels of sirtuin 6 (SIRT6), nuclear factor erythroid 2-related factor 2 (Nrf2), and xanthine oxidoreductase (XOR).

Multiple-Purpose Connectivity Map Analysis Reveals the Benefits of Esculetin to Hyperuricemia and Renal Fibrosis

“…UA administration increased the expression of XO which decreased in response to esculetin treatment ( Figure 5 E). It has been reported that Nrf2 transcriptionally activates XO in glioma cells, which is dependent on Nrf2 and HK2 trafficking to the nucleus [ 17 ]. Esculetin treatment abolished the translocation of HK2 to the nucleus whilst the nuclear import of Nrf2 was upregulated in UA-treated HepG2 cells ( Figure 5 F).…”

“…It has previously been shown that HK2 acts as a transcriptional coactivator of Nrf2 to regulate XO expression. Decreased nuclear translocation in response to HK2 may therefore inhibit XO expression [ 17 ]. We therefore hypothesize that the molecular mechanisms by which esculetin suppresses XO is related to its ability to inhibit the nuclear translocation of HK2 ( Figure 5 F).…”

Down-Regulating Hexokinase 2 Inhibits Proliferation of Endometrial Stromal Cells Through a Noncanonical Pathway Involving Phosphorylated-STAT1 in Endometriosis

“…Studies have shown that various metabolic enzymes in the cytoplasm and mitochondria could translocate into the nucleus to modify histones and DNA, regulating gene expression (42). A report stated HK2 could translocate into the nucleus as a coactivator participating in redox homeostasis (43). In our ndings, HK2 affected the expression and distribution of phosphorylation of STAT1.…”

Mechanisms of Long Non-Coding RNAs in Biological Characteristics and Aerobic Glycolysis of Glioma

“…Hexokinase (HK) is recognized as the first vital enzyme of the glycolytic pathway, which can promote the uptake of glucose into glioma cells via GLUTs by glucose phosphorylation reaction [ 103 ]. Numerous studies reported the upregulation of hexokinase isoform 2 (HK2) in cancer cells and its association with the overall survival of patients with glioma [ 104 , 105 , 106 ]. Zheng et al investigated the mechanism of lncRNA MACC1-AS1-mediated progression of glioma.…”