Plasminogen Activator lnhibitor-1 in Cancer: Rationale and Insight for Future Therapeutic Testing

摘要

Despite its function as an inhibitor of urokinase and tissue-type plasminogen activator (PA), PA inhibitor-1 (PAI-1) has a paradoxical protumorigenic role in cancer, promoting angiogenesis and tumor cell survival. In this review, we summarize predinical evidence in support of the protumorigenic function of PAI-1 that has led to the testing of small-molecule PAI-1 inhibitors, initially developed as antithrombotic agents, in animal models of cancer. The review discusses the challenges and the opportunities that lay ahead to the development of efficacious and nontoxic PAI-1 inhibitors as anticancer agents. Plasminogen activator inhibitor-1 (PAI-1) is a serine protease inhibitor (serpin) and the main regulator of the plasminogen activation system. It acts by inhibiting tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA; ref. 1). PAI-1 has a pleiotropic biologic function that stems from its complex structure. Three specific protein-binding domains in the molecule have been well characterized (Fig. 1; ref. 1): a domain in the reactive center loop (RCL) that binds to PA, a domain in the flexible joint region that binds to vitronectin composed of helix D (hD), helix E (hE), and helix F (hF), and a domain within hD and hE that binds to low-density lipoprotein receptor-related protein (LRP1). Upon binding to the RCL, PA cleaves PAI-1 at Pl-Pl1 inducing a dynamic conformational change that inserts the RCL as a fS-strand (4A) into the core of the protein. The binding of PAI-1 to PA forms a catalytically inactive complex, which is internalized when combined with the receptor for uPA (uPAR) and LRP1 (2). Premature insertion of the RCL into the |3-sheet is the basis for the conversion of active PAI-1 into its latent form.