Interleukin-6 induces vascular endothelial growth factor expression and promotes angiogenesis through apoptosis signal-regulating kinase 1 in human osteosarcoma

• Published in: Biochemical pharmacology Vol. 85; no. 4; pp. 531 - 540
• Main Authors: Tzeng, Huey-En, Tsai, Chun-Hao, Chang, Zi-Ling, Su, Chen-Ming, Wang, Shih-Wei, Hwang, Wen-Li, Tang, Chih-Hsin
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 15.02.2013
• Subjects: Angiogenesis; Antibodies, Monoclonal - immunology; apoptosis; ASK1; Bone Neoplasms - blood supply; Bone Neoplasms - metabolism; Bone Neoplasms - pathology; Cell Differentiation; Cell Line, Tumor; Endothelial Cells - cytology; Endothelial Cells - drug effects; Gene Expression Regulation, Neoplastic - drug effects; Gene Knockdown Techniques; Humans; IL-6; interleukin-6; Interleukin-6 - genetics; Interleukin-6 - metabolism; MAP Kinase Kinase Kinase 5 - metabolism; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - physiology; metastasis; Neovascularization, Pathologic; Osteosarcoma; Osteosarcoma - blood supply; Osteosarcoma - metabolism; Osteosarcoma - pathology; pharmacology; protein synthesis; Real-Time Polymerase Chain Reaction; Receptors, Interleukin-6 - immunology; RNA Interference; RNA, Small Interfering; Signal Transduction - drug effects; Stem Cells - cytology; Stem Cells - drug effects; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism; vascular endothelial growth factors; VEGF; Angiogenesis; Osteosarcoma; VEGF; ASK1; IL-6
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2012.11.021

Osteosarcoma is characterized by a high malignant and metastatic potential. Angiogenesis is essential for the caner metastasis. Interleukin-6 (IL-6) is a multifunctional cytokine that is associated with the disease status and outcomes of cancers. However, the relationship between IL-6 and vascular endothelial growth factor (VEGF) expression in human osteosarcoma is mostly unknown. Here we found that the IL-6 and VEGF expression was correlated with tumor stage and significantly higher than that in normal bone. Incubation of osteosarcoma cells with IL-6 increased VEGF mRNA and protein expression. Pretreatment of cells with IL-6R antibody reduced IL-6-mediated VEGF production. The apoptosis signal-regulating kinase 1 (ASK1)/p38/AP-1 pathway was activated after IL-6 treatment, and IL-6-induced VEGF expression was abolished by the specific inhibitor and siRNA of ASK1, p38, and AP-1 cascades. Importantly, knockdown IL-6 reduced VEGF expression and abolished osteosarcoma conditional medium-mediated angiogenesis. Taken together, these results indicate that IL-6 occurs through ASK1 and p38, which in turn activates AP-1, resulting in the activations of VEGF expression and contributing the angiogenesis of human osteosarcoma cells.