The HIV protease inhibitor indinavir down-regulates the expression of the pro-angiogenic MT1-MMP by human endothelial cells.
In addition to contrast human immunodeficiency virus (HIV) replication, the HIV protease inhibitors (HIV-PI) have reduced tumour incidence or clinical progression in infected patients. In this regard, we have previously shown that, independently of its anti-viral activity, the HIV-PI indinavir (IDV) directly blocks matrix metalloproteinase (MMP)-2 proteolytic activation, thus efficiently inhibiting tumour angiogenesis in vitro, in animal models, and in humans. Herein we investigated the molecular mechanism for IDV anti-angiogenic effect. We found that treatment of human primary endothelial cells with therapeutic IDV concentrations decreases the expression of membrane type (MT)1-MMP, which is the major activator of MMP-2. This occurs for both the constitutive expression of MT1-MMP and that up-regulated by angiogenic factors. In either cases, reduction of MT1-MMP levels by IDV is preceded by the inhibition of the binding of the specificity protein (Sp)1 transcription factor to the promoter region of the MT1-MMP gene in endothelial cell nuclei. As MT1-MMP is key for tumour angiogenesis, these results support the use of IDV or its derivatives in anti-cancer therapy. This is recommended by the low toxicity of the drug, and the large body of data on its pharmacokinetic.
Department of Clinical Sciences and Translational Medicine, University "Tor Vergata", 1 via Montpellier, 00133, Rome, Italy, barillar@uniroma2.it.
Giovanni
G
Barillari
André
A
Iovane
Ilaria
I
Bacigalupo
Catherine
C
Labbaye
Chiara
C
Chiozzini
Leonardo
L
Sernicola
Maria Teresa
MT
Quaranta
Mario
M
Falchi
Cecilia
C
Sgadari
Barbara
B
Ensoli
D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D042783:Endothelial Cells / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D017320:HIV Protease Inhibitors / Q000737:chemistry*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D019469:Indinavir / Q000494:pharmacology*; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic; D011401:Promoter Regions, Genetic; D060888:Real-Time Polymerase Chain Reaction; D016329:Sp1 Transcription Factor / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D017320:HIV Protease Inhibitors; D016329:Sp1 Transcription Factor; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D019469:Indinavir; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14