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

Cell Death & Differentiation (2024)Cite this article

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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.

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Fig. 1: Cuproptosis activates Wnt/β-catenin signaling.
Fig. 2: The SLC31A1-copper axis regulates PDK1/AKT/GSK3β/β-catenin signaling and stemness.
Fig. 3: Activation of Wnt/β-catenin pathway promotes resistance to cuproptosis in cancer stem cells.
Fig. 4: TCF4 protects cancer stem cells from cuproptosis by regulating ATP7B.
Fig. 5: The β-catenin/TCF4 complex activates ATP7B transcription.
Fig. 6: TCF4 deficiency or Wnt signaling inhibition enhances the anticancer activity of elesclomol-Cu in vivo.
Fig. 7: Model for regulation of cuproptosis sensitivity by Wnt/β-catenin signaling in cancer cells.

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Data availability

RNA-seq and CUT&Tag data have been deposited in GEO under the following accession numbers: GSE248083, GSE248084, and GSE248246.

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Funding

This work was financially supported by National Natural Science Foundation of China 82273202, 82072996, 82002893, 82103670, National Key Research and Development Program 2022YFC2504200, Interdisciplinary innovative foundation of Wuhan University XNJC202303, and the Fundamental Research Funds for the Central Universities (2042022dx0003).

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  1. These authors contributed equally: Yuan-Tong Liu, Lei Chen.

Authors and 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

    Yuan-Tong Liu, Lei Chen, Shu-Jin Li, Wu-Yin Wang, Yuan-Yuan Wang, Qi-Chao Yang, An Song, Meng-Jie Zhang, Wen-Tao Mo, Hao Li & Zhi-Jun Sun

  2. Department of Stomatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Chuan-Yu Hu

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Contributions

Y.T. Liu: Data curation, conceptualization, methodology, formal analysis, investigation, writing-original draft. L. Chen: Data curation, methodology, formal analysis, writing-original draft. S.J. Li: Data curation, methodology. W.Y. Wang: Investigation, methodology. Y.Y. Wang: Data curation. Q.C. Yang: Data curation. A. Song: Methodology. M.J. Zhang: Formal analysis. W.T. Mo: Formal analysis. H. Li: Supervision. C.Y. Hu: Writing-review and editing, funding acquisition. Z.J. Sun: Conceptualization, supervision, funding acquisition, writing-original draft, project administration, resources, writing-review and editing.

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Correspondence to Chuan-Yu Hu or Zhi-Jun Sun.

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Approval for human tissue samples utilization was granted by the Medical Ethics Committee of the School and Hospital of Stomatology, Wuhan University (2016LUNSHENZI62), following the guidelines of Declaration of Helsinki. All patients provided written informed consent. All animal experiments were carried out with the approval of the center for Animal Experiment of Wuhan University (WP20230467) and performed according to institutional guidelines.

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Liu, YT., Chen, L., Li, SJ. et al. Dysregulated Wnt/β-catenin signaling confers resistance to cuproptosis in cancer cells. Cell Death Differ (2024). https://doi.org/10.1038/s41418-024-01341-2

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