Glucose starvation to rapid death of Nrf1, but not Nrf2, deficient hepatoma cells from its fatal defects in the redox metabolism reprogramming

Abstract

Metabolic reprogramming exists in a variety of cancer cells, with the most relevance to glucose as a source of energy and carbon for survival and proliferation. Of note, Nrf1 was shown to be essential for regulating glycolysis pathway, but it is unknown whether it plays a role in cancer metabolic reprogramming, particularly in response to glucose starvation.Herein, we discover that Nrf1α / -derived hepatoma cells are sensitive to rapid death induced by glucose deprivation, such cell death appears to be rescued by Nrf2 interference, but Nrf1/2 / or Nrf2 / -derived cells are roughly unaffected by glucose starvation. Further evidence revealed that Nrf1α / cell death is resulted from severe oxidative stress arising from abberrant redox metabolism. Strikingly, altered gluconeogenesis pathway was aggravated by glucose starvation of Nrf1α / cells, as also accompanied by weakened pentose phosphate pathway, dysfunction of serine-to-glutathione synthesis, and accumulation of reactive oxygen species (ROS) and damages, such that the intracellular GSH and NADPH were exhausted. These demonstrate that glucose starvation leads to acute death of Nrf1α / , rather than Nrf2 / , cells resulting from its fatal defects in the redox metabolism reprogramming. This is owing to distinct requirements of Nrf1 and Nrf2 for regulating key genes involved in the redox metabolic reprogramming. Altogether, this work substantiates the preventive and therapeutic strategies against Nrf1α-deficient cancer by limiting its glucose and energy demands.

Dysfunction of an energy sensor NFE2L1 triggers uncontrollable AMPK signal and glucose metabolism reprogramming

“…In NFE2L1 knockdown cells, the ROS level was increased more than 6 times in comparison with the control group after glucose deprivation for 6 hours, indicating the high levels of oxidative damage of NFE2L1 knockdown cells. These results were in accordance with previous studies that glucose starvation resulted in strong oxidative stress to induce cell death after NFE2L1 knockout (Qiu et al, 2018; Zhu et al, 2020).…”

“…Consistent with our results, previous studies had shown that overexpression and knockout of NFE2L1 could change glucose metabolism through different ways such as ROS, insulin secretion, and liver metabolism (Hirotsu et al, 2014; Zheng et al, 2015; Zhu et al, 2020). However, the underlying molecular mechanism by which NFE2L1 affects glucose metabolism remains to be explored.…”

“…1). These results were consistent with previous studies (Zhu et al, 2020). NFE2L1 could negatively regulate glucose uptake (Fig.…”

“…O-glycosylation modification in the Neh6L domain of NFE2L1 can reduce the transcription activity of NFE2L1 protein (Chen et al, 2015). Additionally, in HepG2 cells, deletion of NFE2L1 can cause glucose deprivation, which finally induces cell death (Zhu et al, 2020). These studies suggest that NFE2L1 may be a key factor for regulating glucose metabolism homeostasis by sensing glucose levels.…”

The functions and clinical significance of circRNAs in hematological malignancies

“…Represented by glycolysis, fatty acid oxidation, and amino acid metabolism, metabolic reprogramming is a typical hallmark in cancer cells [50]. Tumor cells are featured by the strong dependence on glycolysis to provide energy despite sufficient oxygen availability [51].…”