Protein C Inhibitor Suppresses Tumor Cell Growth and Metastasis by Inhibiting Angiogenesis

Introduction: Protein C inhibitor (PCI) was initially found in human plasma as an inhibitor of activated protein C (APC), the main protease of the anticoagulant protein C pathway [1]. PCI has a reactive site (354Arg-355Ser), which is important for inhibition of serine proteases; therefore, PCI is categorized as a member of the serine protease inhibitor (SERPIN) family [2]. Subsequent studies revealed that PCI inhibits other serine proteases of the blood coagulation system including thrombin [3], factor Xa [3], factor XIa [4], plasma kallikrein [4], and thrombin-thrombomodulin complex [5], proteases of the fibrinolysis system including tissue plasminogen activator (tPA) [6] and urinary plasminogen activator (uPA) [7], and also proteases of the fertilization system such as prostate-specific antigen (PSA) [8] and sperm acrosin [9]. The main source of human plasma PCI may be the liver because plasma PCI levels are markedly decreased in patients with liver disease [10]. Human PCI mRNA is also detected in kidneys [11] and reproductive organs [12]. Recently, we found that the PCI antigen and mRNA levels are significantly lower in renal cell carcinoma tissues (RCC) than in non-tumoral renal tissues. Subsequently, we demonstrated that normal renal proximal tubular epithelial cells (RPTEC), but not RCC or RCC cell lines (Caki-1), express PCI [13]. In the present study, we evaluated the effect of PCI on tumor growth and metastasis of the human MDA-231 breast cancer cells. The effect of PCI on angiogenesis was also evaluated.