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

Article highlights

• Dysregulation of lysyl oxidases (LOXs) is linked to fibrosis and cancer in a variety of tissues and organs.

• The LOX family of proteins consists of five members and is required for normal biosynthesis of the extracellular matrix.

• Functions of the LOX family of proteins extend beyond the classically known contributions to collagen and elastin cross-linking and include regulation of cell proliferation and differentiation.

• Respective unique domains of LOX family members mediate novel functions and some of these are independent of active LOX enzyme activity.

• The current understanding of contributions of both enzyme-dependent and non-enzyme dependent activities of LOXs to fibrosis and cancer points to the high likelihood of future development of potential therapeutic opportunities. Such opportunities will grow out of an increased mechanistic understanding of the variety of functions of the versatile LOX family.

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Financial and competing interests disclosure

The author was supported by the National Institutes of Health under grant number R21DE023973 from the National Institute of Dental and Craniofacial Research (NIDCR). P Trackman also serves as a consultant for Pharmaxis Corp., Sydney, Australia. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This work was funded in great part by National Science Foundation Grant No. 0732233, “Learning Progressions for Scientific Inquiry: A Model Implementation in the Context of Energy.”