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

By Junmei Yi, Jiajun Zhu, Jiao Wu, Craig B. Thompson, Xuejun Jiang. Proceedings of the National Academy of Sciences of the United States of America, 2020

837 citations recorded by the source corpus.

Significance This work demonstrates that oncogenic activation of the PI3K-AKT-mTOR signaling pathway suppresses ferroptosis via the sterol regulatory element-binding protein-mediated lipogenesis, and that inhibition of this pathway potentiates the cancer therapeutic effect of ferroptosis induction. This finding unveils mechanisms for the regulation of ferroptosis and provides a potential cancer therapeutic approach for treating cancer patients bearing tumorigenic mutations in the PI3K-AKT-mTOR pathway. 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.

Subfields: Cancer Research, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/131de55e35c58d80abe58d7905366ebbd1809576

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In Cancer Research

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Citations in the corpus

• The cell biology of ferroptosis (2024, neutral): “SREBP1-dependent expression of stearoyl-CoA desatu-rase 1 (SCD1) is required for this effect 125 .”
• Ferroptosis in infection, inflammation, and immunity (2021, background): “…further doubly regulated by an amino acid sensor: mechanistic target of rapamycin kinase (Baba et al., 2018; Conlon et al., 2021; Liu et al., 2021; Yi et al., 2020; Zhang et al., 2021) or an energy sensor: adenosine monophosphate–activated protein kinase (AMPK; Lee et al., 2020; Li et al., 2020a;…”
• Ferroptosis in cancer: from molecular mechanisms to therapeutic strategies (2024, background): “217 We also reported that lorlatinib sensitizes ferroptosis by inhibiting PI3K/AKT/mTOR-mediated SREBP1/SCD1 signaling axis via targeting insulin-like growth factor 1 receptor (IGF1R) and synergizes with RSL3 to inhibit melanoma.”
• Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications. (2022, neutral): “, 2021) and increased sterol response element binding protein (SREBP)-mediated lipogenesis (Yi et al., 2020).”
• Ferroptosis surveillance independent of GPX4 and differentially regulated by sex hormones (2023, background): “Targeting of SCD1 is at least partially effective, because SCD1 suppresses ferroptosis by generating MUFAs endogenously.(16,51,52) However, cancer cells might also acquire MUFAs extracellularly if they reside in a MUFA-rich environment—under such condition, targeting SCD1 might not have any therapeu”