期刊
CELL DEATH AND DIFFERENTIATION
卷 29, 期 11, 页码 2190-2202出版社
SPRINGERNATURE
DOI: 10.1038/s41418-022-01008-w
关键词
-
资金
- National Natural Science Foundation of China [82172284, 81772151, 81971901, 82002107, 81871620, 81801983, 81871627]
The activation of the Wnt/β-catenin signaling pathway attenuates lipid ROS production in gastric cancer cells and inhibits ferroptosis. The β-catenin/TCF4 transcription complex induces the expression of GPX4, suppressing ferroptotic cell death. TCF4 deficiency promotes cisplatin-induced ferroptosis.
The development of chemotherapy resistance is the most vital obstacle to clinical efficacy in gastric cancer (GC). The dysregulation of the Wnt/beta-catenin signaling pathway is critically associated with GC development and chemotherapy resistance. Ferroptosis is a form of regulated cell death, induced by an iron-dependent accumulation of lipid peroxides during chemotherapy. However, whether the Wnt/beta-catenin signaling directly controls resistance to cell death, remains unclear. Here, we show that the activation of the Wnt/beta-catenin signaling attenuates cellular lipid ROS production and subsequently inhibits ferroptosis in GC cells. The beta-catenin/TCF4 transcription complex directly binds to the promoter region of GPX4 and induces its expression, resulting in the suppression of ferroptotic cell death. Concordantly, TCF4 deficiency promotes cisplatin-induced ferroptosis in vitro and in vivo. Thus, we demonstrate that the aberrant activation of the Wnt/beta-catenin signaling confers ferroptosis resistance and suggests a potential therapeutic strategy to enhance chemo-sensitivity for advanced GC patients.
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