Unveiling the Role of Tryptophan 2,3-Dioxygenase in the Angiogenic Process

被引:1
|
作者
Cecchi, Marta [1 ]
Anceschi, Cecilia [2 ]
Silvano, Angela [3 ]
Coniglio, Maria Luisa [4 ]
Chinnici, Aurora [1 ,4 ]
Magnelli, Lucia [2 ]
Lapucci, Andrea [5 ]
Laurenzana, Anna [2 ]
Parenti, Astrid [5 ]
机构
[1] Univ Florence, Dept Neurosci Psychol Drug Res & Child Hlth, NEUROFARBA Pharmacol & Toxicol Sect, I-50139 Florence, Italy
[2] Univ Florence, Dept Expt & Clin Biomed Sci Mario Serio, I-50134 Florence, Italy
[3] Univ Florence, Careggi Hosp, Dept Hlth Sci, Div Obstet & Gynecol, I-50139 Florence, Italy
[4] Meyer Childrens Hosp IRCCS, Ctr Excellence, Div Pediat Oncol Hematol, I-50139 Florence, Italy
[5] Univ Florence, Dept Hlth Sci, Clin Pharmacol & Oncol Sect, Viale G Peraccini 6, I-50139 Florence, Italy
关键词
tryptophan 2,3-dioxygenase; angiogenesis; melanoma; kynurenine pathway; endothelial progenitor cells; endothelial cells; metalloproteinases; ENDOTHELIAL PROGENITOR CELLS; CANCER; INHIBITION; PROGRESSION; THERAPY; E2F1; UPAR;
D O I
10.3390/ph17050558
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Background: Indoleamine 2,3-dioxygenase (IDO1) and tryptophan-2,3-dioxygenase (TDO) are the two principals enzymes involved in the catabolization of tryptophan (Trp) into kynurenine (Kyn). Despite their well-established role in the immune escape, their involvement in angiogenesis remains uncertain. We aimed to characterize TDO and IDO1 in human umbilical venular endothelial cells (HUVECs) and human endothelial colony-forming cells (ECFCs). Methods: qRT-PCR and immunofluorescence were used for TDO and IDO1 expression while their activity was measured using ELISA assays. Cell proliferation was examined via MTT tests and in in vitro angiogenesis by capillary morphogenesis. Results: HUVECs and ECFCs expressed TDO and IDO1. Treatment with the selective TDO inhibitor 680C91 significantly impaired HUVEC proliferation and 3D-tube formation in response to VEGF-A, while IDO1 inhibition showed no effect. VEGF-induced mTor phosphorylation and Kyn production were hindered by 680C91. ECFC morphogenesis was also inhibited by 680C91. Co-culturing HUVECs with A375 induced TDO up-regulation in both cell types, whose inhibition reduced MMP9 activity and prevented c-Myc and E2f1 upregulation. Conclusions: HUVECs and ECFCs express the key enzymes of the kynurenine pathway. Significantly, TDO emerges as a pivotal player in in vitro proliferation and capillary morphogenesis, suggesting a potential pathophysiological role in angiogenesis beyond its well-known immunomodulatory effects.
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页数:18
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