Copper chelation inhibits TGF-β pathways and suppresses epithelial-mesenchymal transition in cancer
Poursani, E. M.; Mercatelli, D.; Raninga, P.; Bell, J. L.; Saletta, F.; Kohane, F. V.; Zheng, Y.; Rouaen, J.; Jue, T. R.; Michniewicz, F. T.; Kasiou, E.; Tsoli, M.; Cirillo, G.; Waters, S.; Shai-Hee, T.; Valli, E.; Brettle, M.; Whan, R.; Vahdat, L.; Ziegler, D.; Lock, J. G.; Giorgi, F. M.; Khanna, K. k.; VITTORIO, O.
Show abstract
Copper is a trace element essential to cellular function with elevated levels implicated in cancer progression. Clinical trials using copper chelators are associated with improved patient survival, however, the molecular mechanisms by which copper depletion inhibits tumor progression are poorly understood. This remains a major hurdle to the clinical translation of copper chelators. Epithelial-mesenchymal transition (EMT) is often exploited by malignant cells to promote growth and metastasis. Transforming growth factor (TGF)-{beta} is a master regulator of EMT and facilitates cancer progression through changes in the tumor and its microenvironment. Herein, we report that a reduction of copper with the chelating agent tetraethylenepentamine (TEPA) inhibited EMT in vitro in three diverse cancer cell types; human triple-negative breast cancer (TNBC), neuroblastoma (NB), and diffuse intrinsic pontine glioma (DIPG) cell lines. Single-molecule imaging demonstrated EMT markers including Vimentin, {beta}-catenin, ZEB1, and p-SMAD2 had increased expression with copper treatment and this pro-mesenchymal shift was rescued by the addition of TEPA. Moreover, SNAI1, ZEB1, and p-SMAD2 demonstrated increased accumulation in the cytoplasm after treating with TEPA. Transcriptomic analyses revealed a significant downregulation of the EMT pathway, including canonical (TGF-{beta}/SMAD2&3) and non-canonical (TGF-{beta}/PI3K/AKT and TGF-{beta}/RAS/RAF/MEK/ERK) TGF signaling pathways. Matrix metalloproteinases MMP-9 and MMP-14 proteins which activate latent TGF-{beta} complexes were also downregulated by TEPA treatment. These molecular changes are consistent with reduced plasma levels of TGF-{beta} we observed in cancer models treated with TEPA. Importantly, copper chelation reduced metastasis to the lung in a TNBC orthotopic syngeneic mouse model. Our studies suggest copper chelation therapy can be used to inhibit EMT-induced metastasis by targeting TGF-{beta} signalling. Because on-target anti-TGF-{beta} therapies are failing in the clinic, copper chelation presents itself as a potential therapy for targeting TGF-{beta} in cancer.
Matching journals
The top 7 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- A pro-oxidant combination of resveratrol and copper down-regulates hallmarks of cancer and immune checkpoints in patients with advanced oral cancer: Results of an exploratory study (RESCU 004) 94%
- Modulated TRPC1 expression predicts sensitivity of breast cancer to doxorubicin and magnetic field therapy: segue towards a precision medicine approach. 94%
- ERK3/MAPK6 promotes triple-negative breast cancer progression through collective migration and EMT plasticity 94%
Similar papers in this journal
- Synthetic lethality screening identifies FDA-approved drugs that overcome ATP7B-mediated tolerance of tumor cells to cisplatin 95%
- PRMT1 regulates EGFR and Wnt signaling pathways and is a promising target for combinatorial treatment of breast cancer 95%
- Epigenetic Modulation of SPCA2 Reverses Epithelial to Mesenchymal Transition in Breast Cancer Cells 95%
Similar papers in this journal
- Altering mammalian transcription networking with ADAADi: An inhibitor of ATP-dependent chromatin remodeling 95%
- Evaluation of deacetylase inhibition in metaplastic breast carcinoma using multiple derivations of preclinical models of a new patient-derived tumor 95%
- Geldanamycin treatment does not result in anti-cancer activity in a preclinical model of orthotopic mesothelioma 95%
Similar papers in this journal
- Arsenic hexoxide has differential effects on cell proliferation and genome-wide gene expression in human primary mammary epithelial and MCF7 cells 95%
- Selective Impact of ALK and MELK Inhibition on ERα Stability and Cell Proliferation in Cell Lines Representing Distinct Molecular Phenotypes of Breast Cancer 95%
- Emerin deficiency drives MCF7 cells to an invasive phenotype 94%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.