Copper activates HIF-1α/GPER/VEGF signalling in cancer cells

Abstract

// Damiano Cosimo Rigiracciolo 1 , Andrea Scarpelli 1 , Rosamaria Lappano 1 , Assunta Pisano 1 , Maria Francesca Santolla 1 , Paola De Marco 1 , Francesca Cirillo 1 , Anna Rita Cappello 1 , Vincenza Dolce 1 , Antonino Belfiore 2 , Marcello Maggiolini 1 and Ernestina Marianna De Francesco 1 1 Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy 2 Endocrinology, Department of Health, University Magna Graecia of Catanzaro, Catanzaro, Italy Correspondence to: Marcello Maggiolini, email: // Keywords : copper, cancer, angiogenesis, GPER, HIF-1α, VEGF, Pathology Section Received : June 15, 2015 Accepted : August 31, 2015 Published : September 22, 2015 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 (CuSO 4 ) 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 CuSO 4 . In addition, in human endothelial cells, the conditioned medium from breast cancer cells treated with CuSO 4 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.