Lysyl Oxidase Isoforms and Potential Therapeutic Opportunities for Fibrosis and Cancer

Abstract

Introduction: The lysyl oxidase family of enzymes is classically known as being required for connective tissue maturation by oxidizing lysine residues in elastin and lysine and hydroxylysine residues in collagen precursors. The resulting aldehydes then participate in cross-link formation, which is required for normal connective tissue integrity. These enzymes have biological functions that extend beyond this fundamental biosynthetic role, with contributions to angiogenesis, cell proliferation, and cell differentiation. Dysregulation of lysyl oxidases occurs in multiple pathologies including fibrosis, primary and metastatic cancers, and complications of diabetes in a variety of tissues.

Areas covered: This review summarizes the major findings of novel roles for lysyl oxidases in pathologies, and highlights some of the potential therapeutic approaches that are in development and which stem from these new findings.

Expert opinion: Fundamental questions remain regarding the mechanisms of novel biological functions of this family of proteins, and regarding functions that are independent of their catalytic enzyme activity. However, progress is underway in the development of isoform-specific pharmacologic inhibitors, potential therapeutic antibodies and gaining an increased understanding of both tumor suppressor and metastasis promotion activities. Ultimately, this is likely to lead to novel therapeutic agents.

Keywords: Cancer; copper amine oxidases; fibrosis; lysyl oxidase propeptide; lysyl oxidases; lysyl tyrosylquinone.

Figure 1

The mechanism of action of the lysyl oxidase-catalyzed reaction . The red molecule represents the primary amine substrate or lysine side chain substrate. The numbers identify the sequence of the reaction steps.