Tpl2 Inhibitors Thwart Endothelial Cell Function in Angiogenesis and Peritoneal Dissemination

• Published in: Neoplasia (New York, N.Y.) Vol. 15; no. 9; pp. 1036 - IN4
• Main Authors: Lee, Wen-Jane, Lan, Keng-Hsin, Chou, Chiang-Ting, Yi, Yu-Chiao, Chen, Wei-Chih, Pan, Hung-Chuan, Peng, Yen-Chun, Wang, Keh-Bin, Chen, Yi-Ching, Chao, Te-Hsin, Tien, Hsing-Ru, Sheu, Wayne Huey Herng, Sheu, Meei-Ling
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2013; Elsevier
• Subjects: Activating Transcription Factor 1 - metabolism; Animals; CCAAT-Enhancer-Binding Protein-beta - metabolism; Cell Movement; Cell Proliferation; Chemokine CXCL1 - metabolism; Endothelial Cells - metabolism; Human Umbilical Vein Endothelial Cells - metabolism; Humans; Male; MAP Kinase Kinase Kinases - antagonists & inhibitors; MAP Kinase Kinase Kinases - metabolism; Mice; Mice, Inbred BALB C; Neovascularization, Pathologic - metabolism; NF-kappa B - metabolism; Oncology; Phosphorylation; Proliferating Cell Nuclear Antigen - metabolism; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins - metabolism; RNA Interference; RNA, Small Interfering; Tumor Cells, Cultured; Vascular Endothelial Growth Factor A - metabolism; Xenograft Model Antitumor Assays; C/EBPβ; positron emission tomography/computed tomography; AP1; Tpl2; EGF; VEGF; basic fibroblast growth factor; CXCL1; SVECs; bFGF; mouse microvascular endothelial cells; tumor progression locus 2; NF-κB; chemokine (C-X-C motif) ligand 1; CCAAT/enhancer binding protein β; vascular endothelial growth factor; PET/CT; human umbilical vein endothelial cells; nuclear factor κ light-chain enhancer of activated B cells; activating protein 1; epidermal growth factor; HUVECs
• ISSN: 1476-5586; 1522-8002; 1476-5586; 1522-8002
• DOI: 10.1593/neo.121914

Abstract Angiogenesis is critical in the development of cancer, which involves several angiogenic factors in its peritoneal dissemination. The role of protein tumor progression locus 2 (Tpl2) in angiogenic factor-related endothelial cell angiogenesis is still unclear. To understand the precise mechanism(s) of Tpl2 inhibition in endothelial cells, this study investigated the role of Tpl2 in mediating angiogenic signals using in vitro, in vivo , and ex vivo models. Results showed that inhibition of Tpl2 inhibitor significantly reduced peritoneal dissemination in a mouse model by positron emission tomography/computed tomography imaging. Simultaneously, inhibiting Tpl2 blocked angiogenesis in tumor nodules and prevented angiogenic factor-induced proliferating cell nuclear antigen (PCNA) in endothelial cells. Vascular endothelial growth factor (VEGF) or chemokine (C-X-C motif) ligand 1 (CXCL1) increased Tpl2 kinase activity and phosphorylation in a dose- and time-dependent manner. Furthermore, Tpl2 inhibition or ablation by siRNA prevented the angiogenic signal-induced tube formation in Matrigel plug assay or aortic ring assay. Inhibiting Tpl2 also prevented the angiogenic factor-induced chemotactic motility and migration of endothelial cells. Tpl2 inhibition by CXCL1 or epidermal growth factor in endothelial cells was associated with inactivation of CCAAT/enhancer binding protein β, nuclear factor κ light-chain enhancer of activated B cells, and activating protein 1 and suppression of VEGF expression. Thus, Tpl2 inhibitors thwart Tpl2-regulated VEGF by inactivating transcription factors involved in angiogenic factor-triggered endothelial cell angiogenesis. These results suggest that the therapeutic inhibition of Tpl2 may extend beyond cancer and include the treatment of other diseases involving pathologic angiogenesis.