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

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

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. zengjp@sdu.edu.cn.
  • 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. jiajihui@sdu.edu.cn.
  • 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. jiajihui@sdu.edu.cn.
  • 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. jiajihui@sdu.edu.cn.
  • # 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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