Proteolysis is the most fundamental property of malignancy and its inhibition may be used therapeutically (Review)

Abstract

The mortality rates of cancer patients decreased by ~1.5% per year between 2001 and 2015, although the decrease depends on patient sex, ethnic group and type of malignancy. Cancer remains a significant global health problem, requiring a search for novel treatments. The most common property of malignant tumors is their capacity to invade adjacent tissue and to metastasize, and this cancer aggressiveness is contingent on overexpression of proteolytic enzymes. The components of the plasminogen activation system (PAS) and the metalloproteinase family [mainly matrix metalloproteinases (MMPs)] are overexpressed in malignant tumors, driving the local invasion, metastasis and angiogenesis. This is the case for numerous types of cancer, such as breast, colon, prostate and oral carcinoma, among others. Present chemotherapeutics agents typically attack all dividing cells; however, for future therapeutic agents to be clinically successful, they need to be highly selective for a specific protein(s) and act on the cancerous tissues without adverse systemic effects. Inhibition of proteolysis in cancerous tissue has the ability to attenuate tumor invasion, angiogenesis and migration. For that purpose, inhibiting both PAS and MMPs may be another approach, since the two groups of enzymes are overexpressed in cancer. In the present review, the roles and new findings on PAS and MMP families in cancer formation, growth and possible treatments are discussed.

Figure 1

Diverse functions of plasminogen activation system.

Figure 2

Diverse functions of metalloproteinases. SNP, single-nucleotide polymorphism; MMP, matrix metalloproteinase; TIMP, tissue inhibitor of metal-loproteinase.

Figure 3

Ribbon model of (A) MMP-9 and inhibitors, and (B) uPA and inhibitors. The inhibitors of MMP-9 and uPA are shown as sticks models in red, while ions in MMP-9 are shown as spheres (blue, Zn²⁺; light blue, Ca²⁺; green, Cl⁻). Surface of active site of (C) MMP-9 and (D) uPA. Epigallocatechin gallate is shown as a stick model in light brown. Polar contacts are shown as the yellow dotted lines [reprinted with permission from the study of Jankun et al (113)]. MMP-9, matrix metalloproteinase 9; uPA, urokinase plasminogen activator.

Figure 4

Typical microscopic appearance (reduced from ×40 magnification) of: (A) Control bladder with tumors; (B) tumor-free bladder following treatment with 400 µM epigallocatechin gallate; (C) tumor-free bladder treated with 400 µM MMC; (D) bladder with tumors treated with 400 µM MMC at 3 days after surgery [reprinted with permission from the study of Jankun et al (113)]. MMC, mitomycin C.