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4EBP1-mediated SLC7A11 protein synthesis restrains ferroptosis triggered by MEK inhibitors in advanced ovarian cancer.
- Source :
-
JCI insight [JCI Insight] 2024 Jun 06; Vol. 9 (14). Date of Electronic Publication: 2024 Jun 06. - Publication Year :
- 2024
-
Abstract
- Loss of ferroptosis contributes to the development of human cancer, and restoration of ferroptosis has been demonstrated as a potential therapeutic strategy in cancer treatment. However, the mechanisms of how ferroptosis escape contributes to ovarian cancer (OV) development are not well elucidated. Here, we show that ferroptosis negative regulation signatures correlated with the tumorigenesis of OV and were associated with poor prognosis, suggesting that restoration of ferroptosis represents a potential therapeutic strategy in OV. High-throughput drug screening with a kinase inhibitor library identified MEK inhibitors as ferroptosis inducers in OV cells. We further demonstrated that MEK inhibitor-resistant OV cells were less vulnerable to trametinib-induced ferroptosis. Mechanistically, mTOR/eIF4E binding protein 1 (4EBP1) signaling promoted solute carrier family 7 member 11 (SLC7A11) protein synthesis, leading to ferroptosis inhibition in MEK inhibitor-resistant cells. Dual inhibition of MEK and mTOR/4EBP1 signaling restrained the protein synthesis of SLC7A11 via suppression of the mTOR/4EBP1 axis to reactivate ferroptosis in resistant cells. Together, these findings provide a promising therapeutic option for OV treatment through ferroptosis restoration by the combined inhibition of MEK and mTOR/4EBP1 pathways.
- Subjects :
- Humans
Female
Cell Line, Tumor
Animals
Mice
Cell Cycle Proteins metabolism
Cell Cycle Proteins genetics
Signal Transduction drug effects
Drug Resistance, Neoplasm drug effects
Pyridones pharmacology
Pyridones therapeutic use
Pyrimidinones pharmacology
Pyrimidinones therapeutic use
Ferroptosis drug effects
Ovarian Neoplasms drug therapy
Ovarian Neoplasms pathology
Ovarian Neoplasms metabolism
Ovarian Neoplasms genetics
Amino Acid Transport System y+ metabolism
Amino Acid Transport System y+ genetics
Amino Acid Transport System y+ antagonists & inhibitors
Adaptor Proteins, Signal Transducing metabolism
Adaptor Proteins, Signal Transducing genetics
Protein Kinase Inhibitors pharmacology
Protein Kinase Inhibitors therapeutic use
TOR Serine-Threonine Kinases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2379-3708
- Volume :
- 9
- Issue :
- 14
- Database :
- MEDLINE
- Journal :
- JCI insight
- Publication Type :
- Academic Journal
- Accession number :
- 38842940
- Full Text :
- https://doi.org/10.1172/jci.insight.177857