Arachidonic acid-induced Ca2+ entry is involved in early steps of tumor angiogenesis.
Growth factor-induced intracellular calcium signals in endothelial cells regulate cytosolic and nuclear events involved in the angiogenic process. Among the intracellular messengers released after proangiogenic stimulation, arachidonic acid (AA) plays a key role and its effects are strictly related to calcium homeostasis and cell proliferation. Here, we studied AA-induced intracellular calcium signals in endothelial cells derived from human breast carcinomas (B-TEC). AA promotes B-TEC proliferation and organization of vessel-like structures in vitro. The effect is directly mediated by the fatty acid without a significant contribution of its metabolites. AA induces Ca(2+)(i) signals in the entire capillary-like structure during the early phases of tubulogenesis in vitro. No such responses are detectable in B-TECs organized in more structured tubules. In B-TECs growing in monolayer, AA induces two different signals: a Ca(2+)(i) increase due to Ca(2+) entry and an inhibition of store-dependent Ca(2+) entry induced by thapsigargin or ATP. An inhibitor of Ca(2+) entry and angiogenesis, carboxyamidotriazole, significantly and specifically decreases AA-induced B-TEC tubulogenesis, as well as AA-induced Ca(2+) signals in B-TECs. We conclude that (a) AA-activated Ca(2+) entry is associated with the progression through the early phases of angiogenesis, mainly involving proliferation and tubulogenesis, and it is down-regulated during the reorganization of tumor-derived endothelial cells in capillary-like structures; and (b) inhibition of AA-induced Ca(2+) entry may contribute to the antiangiogenic action of carboxyamidotriazole.
Fiorio Pla
Alessandra
A
Department of Animal and Human Biology, University of Torino, Via Accademia Albertina 13, 10123 Turin, Italy. alessandra.fiorio@unito.it
Grange
Cristina
C
Antoniotti
Susanna
S
Tomatis
Cristiana
C
Merlino
Annalisa
A
Bussolati
Benedetta
B
Munaron
Luca
L
D016718:Arachidonic Acid / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000098:blood supply* / Q000378:metabolism* / Q000473:pathology; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002469:Cell Separation; D006801:Humans; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000473:pathology*; D014230:Triazoles / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D014230:Triazoles; D016718:Arachidonic Acid; C062058:carboxyamido-triazole; D002118:Calcium