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 Nrf1-/--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 Nrf1-/- cell death is resulted from severe oxidative stress arising from abberrant redox metabolism. Strikingly, altered gluconeogenesis pathway was aggravated by glucose starvation of Nrf1-/- 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 Nrf1-/-, 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 Nrf1-deficient cancer by limiting its glucose and energy demands.