Wnt/beta-catenin signaling confers ferroptosis resistance by targeting GPX4 in gastric cancer

  • Cell Death Differ. 2022 May 9. doi: 10.1038/s41418-022-01008-w.
Yue Wang  1  2  3 ,  Lixin Zheng  1  2 ,  Wenjing Shang  3 ,  Zongcheng Yang  3 ,  Tongyu Li  3 ,  Fen Liu  1  2 ,  Wei Shao  1  2 ,  Lin Lv  1  2 ,  Li Chai  1  2 ,  Lingxin Qu  1  2 ,  Qing Xu  1  2 ,  Jie Du  1  2 ,  Xiuming Liang  3  4 ,  Jiping Zeng   #  5 ,  Jihui Jia   #  6  7  8
Affiliations
  • 1. Department of Microbiology/Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, PR China.
  • 2. Key Laboratory of Infection and Immunity of Shandong Province, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, PR China.
  • 3. Shandong University-Karolinska Institute Collaborative Laboratory for Cancer Research, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, PR China.
  • 4. Biomolecular Medicine, Clinical Research Center, Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden.
  • 5. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, PR China. [email protected].
  • 6. Department of Microbiology/Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, PR China. [email protected].
  • 7. Key Laboratory of Infection and Immunity of Shandong Province, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, PR China. [email protected].
  • 8. Shandong University-Karolinska Institute Collaborative Laboratory for Cancer Research, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, PR China. [email protected].
  • # Contributed equally.
PMID: 35534546 DOI: 10.1038/s41418-022-01008-w
Abstract

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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