AKT activation because of PTEN loss upregulates xCT via GSK3β/NRF2, leading to inhibition of ferroptosis in PTEN-mutant tumor cells

Kaitlyn M. Cahuzac, Abigail Lubin, Kaitlyn Bosch, Nicole Stokes, Sarah Mense Shoenfeld, Royce Zhou, Haddy Lemon, John Asara, Ramon E. Parsons

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Here, we show that the tumor suppressor phosphatase and tensin homolog deleted from chromosome 10 (PTEN) sensitizes cells to ferroptosis, an iron-dependent form of cell death, by restraining the expression and activity of the cystine/glutamate antiporter system Xc (xCT). Loss of PTEN activates AKT kinase to inhibit GSK3β, increasing NF-E2 p45-related factor 2 (NRF2) along with transcription of one of its known target genes encoding xCT. Elevated xCT in Pten-null mouse embryonic fibroblasts increases the flux of cystine transport and synthesis of glutathione, which enhances the steady-state levels of these metabolites. A pan-cancer analysis finds that loss of PTEN shows evidence of increased xCT, and PTEN-mutant cells are resistant to ferroptosis as a consequence of elevated xCT. These findings suggest that selection of PTEN mutation during tumor development may be due to its ability to confer resistance to ferroptosis in the setting of metabolic and oxidative stress that occurs during tumor initiation and progression.

Original languageEnglish
Article number112536
JournalCell Reports
Volume42
Issue number5
DOIs
StatePublished - 30 May 2023

Keywords

  • Akt
  • CP: Cancer
  • CP: Metabolism
  • GSK3β
  • NRF2
  • PTEN
  • cancer
  • cysteine
  • ferroptosis
  • glutathione
  • xCT

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