Bisphosphonates suppress insulin‐like growth factor 1‐induced angiogenesis via the HIF‐1α/VEGF signaling pathways in human breast cancer cells

• DOI: 10.1002/ijc.24710
• Publication Date: 2009-06-30T16:31:32Z
• Authors: Xudong Tang; Qunzhou Zhang; Shihong Shi; Yun Yen; Xiangyong Li; Yuefei Zhang; Keyuan Zhou; Anh D. Le
• Keywords: Vascular Endothelial Growth Factor A; 0301 basic medicine; protein synthesis; nitrogen; Phosphatidylinositol 3-Kinases; Breast cancer; 0302 clinical medicine; dose response; phosphatidylinositol 3 kinase; Insulin-Like Growth Factor I; VEGF MeSH: Base Sequence; Tumor; Diphosphonates; Neovascularization, Pathologic; messenger RNA; Reverse Transcriptase Polymerase Chain Reaction; TOR Serine-Threonine Kinases; Bisphosphonates; Immunohistochemistry; 3. Good health; Author keywords: Angiogenesis; priority journal; IGF-1; protein degradation; Hypoxia-Inducible Factor 1; carcinogenesis; Signal Transduction; pamidronic acid; HIF-1α; 610; Breast Neoplasms; Enzyme-Linked Immunosorbent Assay; alpha Subunit; Vascular Endothelial Growth Factor A EMTREE drug terms: clodronic acid; vasculotropin EMTREE medical terms: article; Cell Line; 03 medical and health sciences; Cell Line, Tumor; Humans; controlled study; hypoxia inducible factor 1alpha; human; drug inhibition; protein expression; Neovascularization; mammalian target of rapamycin; DNA Primers; Pathologic; Base Sequence; human cell; Hypoxia-Inducible Factor 1, alpha Subunit; somatomedin C; Dentistry; protein kinase B beta; PI-3K/Akt; Protein Kinases; Proto-Oncogene Proteins c-akt

Abstract Adjunctive chemotherapy with bisphosphonates has been reported to delay bone metastasis and improve overall survival in breast cancer. Aside from its antiresorptive effect, exhibit antitumor activities, vitro vivo , via several mechanisms, including antiangiogenesis. In this study, we investigated the potential molecular mechanisms underlying antiangiogenic effect of non–nitrogen‐containing nitrogen‐containing bisphosphonates, clodronate pamidronate, respectively, insulin‐like growth factor (IGF)‐1 responsive human cancer cells. We tested whether had any effects on hypoxia‐inducible (HIF)‐1α/vascular endothelial (VEGF) axis that plays a pivotal role tumor angiogenesis, our results showed both pamidronate significantly suppressed IGF‐1‐induced HIF‐1α protein accumulation VEGF expression MCF‐7 Mechanistically, found either or did not affect mRNA HIF‐1α, but they apparently promoted degradation protein. Meanwhile, presence led dose‐dependent decease newly‐synthesized induced by IGF‐1 cells after proteasomal inhibition, thus, indirectly reflecting inhibition synthesis. addition, indicated inhibitory HIF‐1α/VEGF are associated phosphoinositide 3‐kinase/AKT/mammalian target rapamycin signaling pathways. Consistently, demonstrated functionally abrogated angiogenesis IGF‐1‐stimulated These findings have highlighted an important mechanism pharmacological action