SGK1 suppresses ferroptosis in ovarian cancer via NRF2-dependent and -independent pathways

Oncogene. 2024 Nov;43(45):3335-3347. doi: 10.1038/s41388-024-03173-3. Epub 2024 Sep 21.

Abstract

High-grade serous ovarian cancer (HGSOC) is a highly aggressive disease often developing resistance to current therapies, necessitating new treatment strategies. Our study identifies SGK1, a key effector in the PI3K pathway, as a promising therapeutic target to exploit ferroptosis, a distinct form of cell death induced by iron overload and lipid peroxidation. Importantly, SGK1 activation, whether through high expression or the constitutively active SGK1-S422D mutation, confers resistance to ferroptosis in HGSOC. Conversely, SGK1 inhibition significantly enhances sensitivity to ferroptosis, as shown by increased PTGS2 expression (a ferroptosis marker), lipid peroxidation, and toxic-free iron levels. Remarkably, this enhanced cytotoxicity is reversed by ferrostatin-1 and the iron chelator deferoxamine, highlighting the pivotal roles of lipid peroxidation and iron dysregulation in the process. Mechanistically, SGK1 protects HGSOC cells from ferroptosis via NRF2-dependent pathways, promoting glutathione synthesis and iron homeostasis, and NRF2-independent pathways via mTOR/SREBP1/SCD1-mediated lipogenesis. Notably, pharmacological SGK1 inhibition sensitizes HGSOC xenograft models to ferroptosis induction, highlighting its therapeutic potential. These findings establish SGK1 as a critical regulator of ferroptosis and suggest targeting SGK1 alongside ferroptosis pathways as a potential therapeutic strategy for HGSOC patients.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Female
  • Ferroptosis* / drug effects
  • Ferroptosis* / genetics
  • Humans
  • Immediate-Early Proteins* / genetics
  • Immediate-Early Proteins* / metabolism
  • Iron / metabolism
  • Lipid Peroxidation / drug effects
  • Mice
  • NF-E2-Related Factor 2* / genetics
  • NF-E2-Related Factor 2* / metabolism
  • Ovarian Neoplasms* / drug therapy
  • Ovarian Neoplasms* / genetics
  • Ovarian Neoplasms* / metabolism
  • Ovarian Neoplasms* / pathology
  • Protein Serine-Threonine Kinases* / genetics
  • Protein Serine-Threonine Kinases* / metabolism
  • Signal Transduction / drug effects

Substances

  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • serum-glucocorticoid regulated kinase
  • Protein Serine-Threonine Kinases
  • Immediate-Early Proteins
  • Iron