2. Academic Validation
  3. Dysregulated Wnt/β-catenin signaling confers resistance to cuproptosis in cancer cells

Dysregulated Wnt/β-catenin signaling confers resistance to cuproptosis in cancer cells

  • Cell Death Differ. 2024 Jul 10. doi: 10.1038/s41418-024-01341-2.
Yuan-Tong Liu # 1,  Lei Chen # 1,  Shu-Jin Li 1,  Wu-Yin Wang 1,  Yuan-Yuan Wang 1,  Qi-Chao Yang 1,  An Song 1,  Meng-Jie Zhang 1,  Wen-Tao Mo 1,  Hao Li 1,  Chuan-Yu Hu 2,  Zhi-Jun Sun 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, China.
  • 2 Department of Stomatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. chuanyuhu@hust.edu.cn.
  • 3 State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, China. sunzj@whu.edu.cn.
  • # Contributed equally.
PMID: 38987382 DOI: 10.1038/s41418-024-01341-2
Abstract

Cuproptosis is characterized by the aggregation of lipoylated Enzymes of the tricarboxylic acid cycle and subsequent loss of iron-sulfur cluster proteins as a unique copper-dependent form of regulated cell death. As dysregulation of copper homeostasis can induce Cuproptosis, there is emerging interest in exploiting Cuproptosis for Cancer therapy. However, the molecular drivers of Cancer cell evasion of Cuproptosis were previously undefined. Here, we found that Cuproptosis activates the Wnt/β-catenin pathway. Mechanistically, copper binds PDK1 and promotes its interaction with Akt, resulting in activation of the Wnt/β-catenin pathway and Cancer stem cell (CSC) properties. Notably, aberrant activation of Wnt/β-catenin signaling conferred resistance of CSCs to Cuproptosis. Further studies showed the β-catenin/TCF4 transcriptional complex directly binds the ATP7B promoter, inducing its expression. ATP7B effluxes copper ions, reducing intracellular copper and inhibiting Cuproptosis. Knockdown of TCF4 or pharmacological Wnt/β-catenin blockade increased the sensitivity of CSCs to elesclomol-Cu-induced Cuproptosis. These findings reveal a link between copper homeostasis regulated by the Wnt/β-catenin pathway and Cuproptosis sensitivity, and suggest a precision medicine strategy for Cancer treatment through selective Cuproptosis induction.

Figures
Products
Inhibitors & Agonists