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Research Articles: Therapeutics, Targets, and Development

Plasminogen activator inhibitor-1 inhibits prostate tumor growth through endothelial apoptosis

¹ Departments of Pharmacology and Molecular Therapeutics and Medicine, Roswell Park Cancer Institute, Buffalo, New York, and ² Quintessence Biotechnology, LLC, Amherst, New York

Requests for reprints: Michael K.K. Wong, Departments of Pharmacology and Molecular Therapeutics and Medicine, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263. Phone: 716-845-7611; Fax: 716-845-4542. E-mail: Michael.Wong{at}RoswellPark.org

Abstract

Plasminogen activator inhibitor-1 (PAI-1) is an important endogenous inhibitor of urokinase-type plasminogen activator. Its action in tumor angiogenesis is complicated, varying with experimental setting and its cellular origin. To further understand the mechanism of the effect of PAI-1 on tumor angiogenesis, especially newly established tumor vasculature in early tumor progression, stable transfectants (TO-PAI-1) of the human prostate adenocarcinoma, PC3, were generated in which PAI-1 expression is under the control of the tetracycline-responsive promoter (Tet-On system). The TO-PAI-1 transfectants exhibit tight inducibility of expression of biologically active PAI-1 in vitro. Induction of PAI-1 expression in nude mice resulted in significant inhibition of tumor growth. This inhibition appears to be due to the effect of PAI-1 on angiogenesis, because it is manifested by an initial wave of tumor endothelial apoptosis accompanied by induction of tumor cell apoptosis and inhibition of tumor cell proliferation. Similar endothelial apoptosis is observed in vitro when human microvascular endothelial cells are physically cocultivated with TO-PAI-1 cells on vitronectin-coated plate. Taken together, these data show for the first time that PAI-1 induces endothelial apoptosis in the newly established tumor vasculature. [Mol Cancer Ther 2008;7(5):1227–10]

Grant support: Department of Medicine Development Funds.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 1/22/08; revised 3/ 5/08; accepted 3/ 6/08.