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JCI insight

IF: 6.1
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4EBP1-mediated SLC7A11 protein synthesis restrains ferroptosis triggered by MEK inhibitors in advanced ovarian cancer

Published:6 June 2024 DOI: 10.1172/jci.insight.177857 PMID: 38842940
Jiaxin Yin,?Jianfeng Chen,?Jing Han Hong,?Yulin Huang,?Rong Xiao,?Shini Liu,?Peng Deng,?Yichen Sun,?Kelila Xin Ye Chai,?Xian Zeng,?Jason Yongsheng Chan,?Peiyong Guan,?Yali Wang,?Peili Wang,?Chongjie Tong,?Qiang Yu,?Xiaojun Xia,?Choon Kiat Ong,?Bin Tean Teh,?Ying Xiong,?Jing Tan

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.

Substances (22)

Materials
Procduct Name CAS Molecular Formula Supplier Price
Geneticin 108321-42-2 C20H42N4O14S 642 suppliers $24.00-$5002.50
Geneticin 108321-42-2 C20H42N4O14S 642 suppliers $24.00-$5002.50
Geneticin 108321-42-2 C20H42N4O14S 642 suppliers $24.00-$5002.50
Geneticin 108321-42-2 C20H42N4O14S 642 suppliers $24.00-$5002.50
Trametinib 871700-17-3 C26H23FIN5O4 380 suppliers $28.00-$4391.10
Trametinib 871700-17-3 C26H23FIN5O4 380 suppliers $28.00-$4391.10
Trametinib 871700-17-3 C26H23FIN5O4 380 suppliers $28.00-$4391.10
Trametinib 871700-17-3 C26H23FIN5O4 380 suppliers $28.00-$4391.10
MK-2206 2HCl 1032350-13-2 C25H22ClN5O 266 suppliers $10.00-$5132.00
MK-2206 2HCl 1032350-13-2 C25H22ClN5O 266 suppliers $10.00-$5132.00

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