Autocrine VEGF is necessary for endothelial survival, although the cellular mechanisms supporting this function are unknown. Here, we show that -even after full differentiation and maturation -continuous expression of VEGF by endothelial cells is needed to sustain vascular integrity and cellular viability. Depletion of VEGF from the endothelium results in mitochondria fragmentation and suppression of glucose metabolism, leading to increased autophagy that contributes to cell death. Gene-expression profiling showed that endothelial VEGF contributes to the regulation of cell cycle and mitochondrial gene clusters, as well as several -but not all -targets of the transcription factor FOXO1. Indeed, VEGF-deficient endothelium in vitro and in vivo showed increased levels of FOXO1 protein in the nucleus and cytoplasm. Silencing of FOXO1 in VEGF-depleted cells reversed expression profiles of several of the gene clusters that were de-regulated in VEGF knockdown, and rescued both cell death and autophagy phenotypes. Our data suggest that endothelial VEGF maintains vascular homeostasis through regulation of FOXO1 levels, thereby ensuring physiological metabolism and endothelial cell survival.
Vascular endothelial growth inhibitor (VEGI), also known as tumor necrosis factor superfamily member 15 or TNF ligand-related molecule 1, is identified as one kind of antiangiogenic cytokine that belongs to the tumor necrosis factor superfamily. VEGI includes three isoforms: VEGI-174, VEGI-192, and VEGI-251. VEGI can activate multiple signaling pathways including nuclear factor-kappaB, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase. Moreover, it suppresses endothelial cell proliferation, angiopoiesis, and tumor growth. Genetic engineering techniques have been used to produce recombinant human vascular endothelial growth inhibitor, and great progress has been made in its application for curing cancer. VEGI could serve as a potential target in the development of angiogenesis-based cancer therapy, and this paper briefly summarizes the progress of the research on VEGI.
This study explored the anticancer activity of C24H20N2O7 [(E)-N- (1-(6-acetyl-7,9-dihydroxy-8,9b-dimethyl-1,3-dioxo-3,9bdihydrodibenzo [b,D]furan-2(1-h)-alkylene)ethyl)isonicotinamide], a novel chemical compound modified by esterification of C18H17NO6. MTT assays, colony formation assays, and flow cytometry analyses were performed to investigate the effect of C24H20N2O7 on the proliferation and apoptosis of HepG2 cells in vitro. A xenograft model in nude mice using HepG2 cells was established to validate the effects of C24H20N2O7 in vitro. The results revealed that the proliferation inhibition rate and the apoptosis rate of HepG2 cells were significantly increased in vitro compared with the control group. C24H20N2O7 treatment also inhibited the volume and mass of HepG2 cell mouse xenografts in vivo, and the body weight and the primary organ coefficient did not differ significantly from the control group. C24H20N2O7 may exert its effects through regulation of autophagy, reactive oxygen species, and endoplasmic reticulum regulated apoptosis. These results indicated that C24H20N2O7 inhibited the proliferation of HepG2 cells and promoted their apoptosis, whilst exhibiting low toxicity in vitro and in vivo. RezumatÎn cadrul acestui studiu am evaluat activitatea anticancerigenă a C24H20N2O7 [(E)-N- (1-(6-(6-acetil-7,9-dihidroxi-8,9b-dimetil-1,3-dioxo-3,9b-dihidrodibenzo [b,D]furan-2(1-h)-alchilen)etil)izonicotinamidă], un compus chimic nou obținut prin esterificarea C18H17NO6. S-au efectuat teste MTT, teste de formare de colonii și analize prin citometrie în flux pentru a investiga efectul C24H20N2O7 asupra proliferării și apoptozei celulelor HepG2 in vitro. Pentru a valida efectele C24H20N2O7 in vitro, a fost stabilit un model de xenogrefă la șoareci folosind celule HepG2. Rezultatele au arătat că rata de inhibare a proliferării și rata de apoptoză a celulelor HepG2 au crescut semnificativ in vitro în comparație cu grupul de control. Tratamentul cu C24H20N2O7 a inhibat, de asemenea, volumul și masa xenogrefelor la șoareci, iar greutatea corporală nu a fost semnificativ diferită față de grupul de control. C24H20N2O7 își poate exercita efectele prin reglarea autofagiei, a speciilor reactive de oxigen și a apoptozei. Aceste rezultate au indicat că C24H20N2O7 a inhibat proliferarea celulelor HepG2 și a indus apoptoza acestora, prezentând în același timp o toxicitate scăzută in vitro și in vivo.
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