Hypoxia-inducible transcription factor-1 alpha determines sensitivity of endothelial cells to the proteosome inhibitor bortezomib.
Angiogenesis is a complex, orchestrated process that plays a critical role in several conditions and has special relevance in the progression of cancer. Hypoxia is the major stimulus for angiogenesis, and hypoxia-inducible transcription factor-1 alpha (HIF-1alpha) is its key mediator. We set up a novel in vitro model of HIF-1alpha up-regulation by treating human umbilical vein endothelial cells (HUVECs) with the hypoxia-mimicking deferoxamine (DFO) and found that this condition was sufficient to promote angiogenesis, like the well-known HUVEC model cultured under low pO(2.) The proteasome inhibitor bortezomib, which induces strong apoptosis in cancer cells, abrogated proliferation and angiogenesis of HUVECs when used at a high concentration (100 nM), yet promoted both functions at a low dosage (10 nM). This double-edged effect appeared to be mediated by differential effects exerted by the different concentrations of bortezomib on 2 master regulators of tumor-associated angiogenesis, HIF-1alpha and nuclear factor kappa B (NF-kB). Significantly, when HUVECs were induced to express HIF-1alpha prior to bortezomib treatment, proliferative and angiogenic responses were abolished, and a greatly enhanced proapoptotic effect was promoted with both concentrations of the drug. These findings indicate that HIF-1alpha up-regulation may sensitize endothelial cells to the antiangiogenic and proapoptotic effects of bortezomib and might be exploited to target tumor-associated vessels in the course of antiangiogenic therapies.
Veschini
Lorenzo
L
Laboratory of Tumor Immunology and Department of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) H San Raffaele, Milan, Italy.
Belloni
Daniela
D
Foglieni
Chiara
C
Cangi
Maria Giulia
MG
Ferrarini
Marina
M
Caligaris-Cappio
Federico
F
Ferrero
Elisabetta
E
D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects; D011480:Protease Inhibitors / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000494:pharmacology*; D012680:Sensitivity and Specificity; D015854:Up-Regulation
D001897:Boronic Acids; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016328:NF-kappa B; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex