Copper activates HIF-1α/GPER/VEGF signalling in cancer cells.
Copper activates HIF-1α/GPER/VEGF signalling in cancer cells.
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DOI：
10.18632/oncotarget.5779
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发表时间：
2015-10-27
期刊：
影响因子：
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通讯作者：
De Francesco EM
中科院分区：
文献类型：
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作者：
Rigiracciolo DC;Scarpelli A;Lappano R;Pisano A;Santolla MF;De Marco P;Cirillo F;Cappello AR;Dolce V;Belfiore A;Maggiolini M;De Francesco EM
铜促进肿瘤血管生成，但其机制仍有待充分了解。我们最近发现G蛋白雌激素受体（GPER）与缺氧诱导因子-1 α（HIF-1α）协同调节促血管生成因子VEGF。在此，我们发现硫酸铜（CuSO 4）通过激活EGFR/ERK/c-fos转导通路诱导乳腺癌和肝癌细胞中HIF-1α以及GPER和VEGF的表达。值得注意的是，铜螯合剂TEPA和ROS清除剂NAC阻止了上述刺激作用。我们还确定HIF-1α和GPER是CuSO 4诱导VEGF转录激活所必需的。此外，在人内皮细胞中，用CuSO 4处理的乳腺癌细胞的条件培养基通过HIF-1α和GPER促进细胞迁移和管形成。目前的研究结果提供了新的见解铜参与触发血管生成和肿瘤进展的分子机制。我们的数据拓宽了铜螯合剂对肿瘤血管生成和进展的治疗潜力。
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.