Nrf2 Redirects Glucose and Glutamine into Anabolic Pathways in Metabolic Reprogramming

SummaryCancer cells consume large quantities of nutrients and maintain high levels of anabolism. Recent studies revealed that various oncogenic pathways are involved in modulation of metabolism. Nrf2, a key regulator for the maintenance of redox homeostasis, has been shown to contribute to malignant phenotypes of cancers including aggressive proliferation. However, the mechanisms with which Nrf2 accelerates proliferation are not fully understood. Here, we show that Nrf2 redirects glucose and glutamine into anabolic pathways, especially under the sustained activation of PI3K-Akt signaling. The active PI3K-Akt pathway augments the nuclear accumulation of Nrf2 and enables Nrf2 to promote metabolic activities that support cell proliferation in addition to enhancing cytoprotection. The functional expansion of Nrf2 reinforces the metabolic reprogramming triggered by proliferative signals.

Graphical AbstractFigure optionsDownload high-quality image (437 K)Download as PowerPoint slideHighlights
► Nrf2 promotes purine nucleotide synthesis and glutamine use in proliferating cells
► Nrf2 directly activates metabolic genes under active PI3K-Akt signaling
► Sustained activation of the PI3K-Akt pathway increases the nuclear availability of Nrf2
► Enhanced cytoprotection and anabolism underlie the Nrf2-mediated cell proliferation