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.

Recent Advances on the Role of G Protein-Coupled Receptors in Hypoxia-Mediated Signaling

“…These observations were further corroborated by the involvement of HIF-1α/GPER signaling in VEGF expression toward tumor angiogenesis and progression (31,89). In addition, HIF-1α/GPER/VEGF transduction pathway was triggered in cancer cells upon exposure to copper, which showed the ability to mimic the hypoxia-mediated signaling (90). Interestingly, the copper-chelating agent TEPA exerted an inhibitory action on the activation of the aforementioned pathway (90), in accordance with previous studies demonstrating that copper-chelating agents can exert anti-tumor effects (91).…”

Characterization of Human and Yeast Mitochondrial Glycine Carriers with Implications for Heme Biosynthesis and Anemia

“…The HEM25 open reading frame was amplified from S. cerevisiae genomic DNA by PCR using primers corresponding to the extremities of the coding sequences with additional NdeI and HindIII sites (5Ј-AAGCTTCATATGACTGAGCAAGCAAC-TAA-3Ј as the forward primer and 5Ј-GAATTCAAGCTTGA-ATCTTTTGACCAACTCCT-3Ј as the reverse primer, respectively). The coding sequence of the human SLC25A38 gene was obtained by RT-PCR reaction using total RNA extracted from HepG2 cells as template (44,45) and the primers with additional NdeI and HindIII sites (5Ј-AAGCTTCATATGAT-TCAGAACTCACGTCC-3Ј and 5Ј-GAATTCAAGCTTGGA-CTTCAGGCCCATCTTGG-3Ј, respectively). The amplified products were cloned into the NdeI-HindIII sites of the expression vector pET21b that had been previously modified by cloning into HindIII-XhoI sites a cDNA sequence coding for a V5 epitope followed by six histidines (46).…”

The Inorganic Perspective of VEGF: Interactions of Cu2+ with Peptides Encompassing a Recognition Domain of the VEGF Receptor

“…Recently, copper sulfate induction has been reported [62] both of the HIF-1α and of G-protein estrogen receptor (GPER) and VEGF expression, in breast and hepatic cancer cells, through the activation of the EGFR/ERK/c-fos transduction pathway.…”

“…A proliferation assay have been carried out in HUVECs with a copper concentration of 500 μM [63], in the presence of fibronectin, which is a protein able not only to bind metal ions but also to act as a transducer of signal for migration and neovascularisation [68]. In addition, the ability of CuSO 4 (200 μM) to up-regulate the mRNA expression of HIF-1a and VEGF in tumor cell lines resulted to be time-dependent, the control level decreasing within 24 h [62].…”