Oncogenic activation of PI3K-AKT-mTOR signaling suppresses ferroptosis via SREBP-mediated lipogenesis Journal Article

Authors: Yi, J.; Zhu, J.; Wu, J.; Thompson, C. B.; Jiang, X.
Article Title: Oncogenic activation of PI3K-AKT-mTOR signaling suppresses ferroptosis via SREBP-mediated lipogenesis
Abstract: Ferroptosis, a form of regulated necrosis driven by iron-dependent peroxidation of phospholipids, is regulated by cellular metabolism, redox homeostasis, and various signaling pathways related to cancer. In this study, we found that activating mutation of phosphatidylinositol 3-kinase (PI3K) or loss of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) function, highly frequent events in human cancer, confers ferroptosis resistance in cancer cells, and that inhibition of the PI3K-AKT-mTOR signaling axis sensitizes cancer cells to ferroptosis induction. Mechanistically, this resistance requires sustained activation of mTORC1 and the mechanistic target of rapamycin (mTOR)C1-dependent induction of sterol regulatory element-binding protein 1 (SREBP1), a central transcription factor regulating lipid metabolism. Furthermore, stearoyl-CoA desaturase-1 (SCD1), a transcriptional target of SREBP1, mediates the ferroptosis-suppressing activity of SREBP1 by producing monounsaturated fatty acids. Genetic or pharmacologic ablation of SREBP1 or SCD1 sensitized ferroptosis in cancer cells with PI3K-AKT-mTOR pathway mutation. Conversely, ectopic expression of SREPB1 or SCD1 restored ferroptosis resistance in these cells, even when mTORC1 was inhibited. In xenograft mouse models for PI3K-mutated breast cancer and PTEN-defective prostate cancer, the combination of mTORC1 inhibition with ferroptosis induction resulted in near-complete tumor regression. In conclusion, hyperactive mutation of PI3K-AKT-mTOR signaling protects cancer cells from oxidative stress and ferroptotic death through SREBP1/ SCD1-mediated lipogenesis, and combination of mTORC1 inhibition with ferroptosis induction shows therapeutic promise in preclinical models. © 2020 National Academy of Sciences. All rights reserved.
Keywords: controlled study; unclassified drug; gene mutation; human cell; drug potentiation; nonhuman; antineoplastic agent; mouse; animal tissue; breast cancer; animal experiment; animal model; tumor regression; tumor xenograft; phosphatidylinositol 3 kinase; temsirolimus; prostate cancer; cancer cell; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; oxidative stress; mammalian target of rapamycin inhibitor; doxycycline; lipid peroxidation; sterol regulatory element binding protein 1; lipogenesis; mtor; mammalian target of rapamycin complex 1; akt signaling; sterol regulatory element binding protein; ferroptosis; 8 [4 (1 aminocyclobutyl)phenyl] 9 phenyl 1,2,4 triazolo[3,4 f][1,6]naphthyridin 3(2h) one; pictilisib; cancer; human; male; female; priority journal; article; oxidoreductase inhibitor; bt-474 cell line; imidazole ketone erastin; phospholipid hydroperoxide glutathione peroxidase; srebp1; acyl coenzyme a desaturase 1; rsl3; torin; mda-mb-453 cell line
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Volume: 117
Issue: 49
ISSN: 0027-8424
Publisher: National Academy of Sciences  
Date Published: 2020-12-08
Start Page: 31189
End Page: 31197
Language: English
DOI: 10.1073/pnas.2017152117
PUBMED: 33229547
PROVIDER: scopus
PMCID: PMC7733797
Notes: Article -- Export Date: 4 January 2021 -- Source: Scopus
Citation Impact
MSK Authors
  1. Xuejun Jiang
    100 Jiang
  2. Craig Bernie Thompson
    141 Thompson
  3. Junmei Yi
    4 Yi
  4. Jiajun Zhu
    6 Zhu
  5. Jiao Wu
    4 Wu