Kallistatin suppresses cancer development by multi-factorial actions

Kallistatin was first identified in human plasma as a tissue kallikrein-binding protein and a serine proteinase inhibitor. Kallistatin via its two structural elements regulates differential signaling cascades, and thus a wide spectrum of biological functions. Kallistatin's active site is essential for: inhibiting tissue kallikrein's activity; stimulating endothelial nitric oxide synthase and sirtuin 1 expression and activation; and modulating the synthesis of the microRNAs, miR-34a, miR-21 and miR-203. Kallistatin's heparin-binding site is crucial for antagonizing the signaling pathways of vascular endothelial growth factor, tumor necrosis factor-α, Wnt, transforming growth factor-β and epidermal growth factor. Circulating kallistatin levels are markedly reduced in patients with prostate and colon cancer. Kallistatin administration attenuates angiogenesis, inflammation, tumor growth and invasion in animal models and cultured cells. Therefore, tumor progression may be substantially suppressed by kallistatin's pleiotropic activities. In this review, we will discuss the role and mechanisms of kallistatin in the regulation of cancer development.