Cell & Bioscience (Jul 2023)

Copper chelation suppresses epithelial-mesenchymal transition by inhibition of canonical and non-canonical TGF-β signaling pathways in cancer

  • Ensieh M. Poursani,
  • Daniele Mercatelli,
  • Prahlad Raninga,
  • Jessica L. Bell,
  • Federica Saletta,
  • Felix V. Kohane,
  • Daniel P. Neumann,
  • Ye Zheng,
  • Jourdin R. C. Rouaen,
  • Toni Rose Jue,
  • Filip T. Michniewicz,
  • Piper Schadel,
  • Erin Kasiou,
  • Maria Tsoli,
  • Giuseppe Cirillo,
  • Shafagh Waters,
  • Tyler Shai-Hee,
  • Riccardo Cazzoli,
  • Merryn Brettle,
  • Iveta Slapetova,
  • Maria Kasherman,
  • Renee Whan,
  • Fernando Souza-Fonseca-Guimaraes,
  • Linda Vahdat,
  • David Ziegler,
  • John G. Lock,
  • Federico M. Giorgi,
  • KumKum Khanna,
  • Orazio Vittorio

DOI
https://doi.org/10.1186/s13578-023-01083-7
Journal volume & issue
Vol. 13, no. 1
pp. 1 – 19

Abstract

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Abstract Background Metastatic cancer cells exploit Epithelial-mesenchymal-transition (EMT) to enhance their migration, invasion, and resistance to treatments. Recent studies highlight that elevated levels of copper are implicated in cancer progression and metastasis. Clinical trials using copper chelators are associated with improved patient survival; however, the molecular mechanisms by which copper depletion inhibits tumor progression and metastasis are poorly understood. This remains a major hurdle to the clinical translation of copper chelators. Here, we propose that copper chelation inhibits metastasis by reducing TGF-β levels and EMT signaling. Given that many drugs targeting TGF-β have failed in clinical trials, partly because of severe side effects arising in patients, we hypothesized that copper chelation therapy might be a less toxic alternative to target the TGF-β/EMT axis. Results Our cytokine array and RNA-seq data suggested a link between copper homeostasis, TGF-β and EMT process. To validate this hypothesis, we performed single-cell imaging, protein assays, and in vivo studies. Here, we used the copper chelating agent TEPA to block copper trafficking. Our in vivo study showed a reduction of TGF-β levels and metastasis to the lung in the TNBC mouse model. Mechanistically, TEPA significantly downregulated canonical (TGF-β/SMAD2&3) and non-canonical (TGF-β/PI3K/AKT, TGF-β/RAS/RAF/MEK/ERK, and TGF-β/WNT/β-catenin) TGF-β signaling pathways. Additionally, EMT markers of MMP-9, MMP-14, Vimentin, β-catenin, ZEB1, and p-SMAD2 were downregulated, and EMT transcription factors of SNAI1, ZEB1, and p-SMAD2 accumulated in the cytoplasm after treatment. Conclusions Our study suggests that copper chelation therapy represents a potentially effective therapeutic approach for targeting TGF-β and inhibiting EMT in a diverse range of cancers.

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