title: Copper activates HIF-1α/GPER/VEGF signalling in cancer cells.
abstract: Copper promotes tumor angiogenesis, nevertheless the mechanisms involved remain to be fully understood. We have recently demonstrated that the G-protein estrogen receptor (GPER) cooperates with hypoxia inducible factor-1α (HIF-1α) toward the regulation of the pro-angiogenic factor VEGF. Here, we show that copper sulfate (CuSO4) induces the expression of HIF-1α as well as GPER and VEGF in breast and hepatic cancer cells through the activation of the EGFR/ERK/c-fos transduction pathway. Worthy, the copper chelating agent TEPA and the ROS scavenger NAC prevented the aforementioned stimulatory effects. We also ascertained that HIF-1α and GPER are required for the transcriptional activation of VEGF induced by CuSO4. In addition, in human endothelial cells, the conditioned medium from breast cancer cells treated with CuSO4 promoted cell migration and tube formation through HIF-1α and GPER. The present results provide novel insights into the molecular mechanisms involved by copper in triggering angiogenesis and tumor progression. Our data broaden the therapeutic potential of copper chelating agents against tumor angiogenesis and progression.
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy.
authors.forename: Damiano Cosimo
authors.initials: DC
authors.lastname: Rigiracciolo
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Scarpelli
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy.
authors.forename: Rosamaria
authors.initials: R
authors.lastname: Lappano
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy.
authors.forename: Assunta
authors.initials: A
authors.lastname: Pisano
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy.
authors.forename: Maria Francesca
authors.initials: MF
authors.lastname: Santolla
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: De Marco
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Cirillo
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy.
authors.forename: Anna Rita
authors.initials: AR
authors.lastname: Cappello
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy.
authors.forename: Vincenza
authors.initials: V
authors.lastname: Dolce
authors.affiliation: Endocrinology, Department of Health, University Magna Graecia of Catanzaro, Catanzaro, Italy.
authors.forename: Antonino
authors.initials: A
authors.lastname: Belfiore
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: Maggiolini
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy.
authors.forename: Ernestina Marianna
authors.initials: EM
authors.lastname: De Francesco
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D019327:Copper Sulfate / Q000633:toxicity*; D005455:Fluorescent Antibody Technique; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D059467:Transcriptome; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: C109584:GPER1 protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D019327:Copper Sulfate
keywords: GPER; HIF-1α; Pathology Section; VEGF; angiogenesis; cancer; copper