Lysyl oxidase
Template:PBB Lysyl oxidase also known as protein-lysine 6-oxidase is a protein that, in humans, is encoded by the LOX gene.[1][2] Its inhibition can cause lathyrism, but, at the same time, its upregulation by tumor cells may promote metastasis of the existing tumor, causing it to become malignant and cancerous.
Function
Lysyl oxidase is an extracellular copper enzyme that catalyzes formation of aldehydes from lysine residues in collagen and elastin precursors.[3][4] These aldehydes are highly reactive, and undergo spontaneous chemical reactions with other lysyl oxidase-derived aldehyde residues, or with unmodified lysine residues. This results in cross-linking collagen and elastin, which is essential for stabilization of collagen fibrils and for the integrity and elasticity of mature elastin.[1]
Complex cross-links are formed in collagen (pyridinolines derived from three lysine residues) and in elastin (desmosines derived from four lysine residues) that differ in structure.[5]
The importance of lysyl oxidase-derived cross-linking was established from animal studies in which lysyl oxidase was inhibited either by nutritional copper-deficiency or by supplementation of diets with β-aminopropionitrile (BAPN), an inhibitor of lysyl oxidase.[6] This resulted in lathyrism, characterized by poor bone formation and strength, hyperextensible skin, weak ligaments, and increased occurrence of aortic aneurysms. These abnormalities correlated well with decreased cross-linking of collagen and elastin.[7]
Clinical significance
LOX expression is regulated by hypoxia-inducible factors (HIFs), and, hence, LOX expression is often upregulated in hypoxic breast and head and neck tumors. Patients with high LOX-expressing tumors have poor overall survival. Furthermore, inhibition of LOX has been demonstrated to eliminate metastases in mice. Secreted LOX is responsible for the invasive properties of hypoxic cancer cells through focal adhesion kinase activity and cell-to-matrix adhesion. LOX may be required to create a niche permissive for metastatic growth and, thus, may be required for hypoxia-induced metastasis.[8]
In a rodent model of breast cancer, a small-molecule or antibody inhibitors of LOX abolished metastasis.[9] LOX secreted by hypoxic breast tumor cells crosslinks collagen in the basement membrane and is essential for CD11b+ myeloid cell recruitment. CD11b+ cells in turn adhere to crosslinked collagen and produce matrix metalloproteinase-2, which cleaves collagen, enhancing the invasion of metastasizing tumor cells. In contrast, LOX inhibition prevents CD11b+ cell recruitment and metastatic growth.[10]
Hence, inhibitors of the LOX enzyme may be useful in preventing tumor progression and metastasis as well as treating other fibrotic disease involving remodeling of the extracellular matrix, including neurodegenerative and cardiovascular diseases.[11]
See also
References
- ^ a b "Entrez Gene: LOX lysyl oxidase".
- ^ Hämäläinen ER, Jones TA, Sheer D, Taskinen K, Pihlajaniemi T, Kivirikko KI (1991). "Molecular cloning of human lysyl oxidase and assignment of the gene to chromosome 5q23.3-31.2". Genomics. 11 (3): 508–16. doi:10.1016/0888-7543(91)90057-L. PMID 1685472.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Alberts, Bruce (2002). Molecular biology of the cell. New York: Garland Science. p. 1099. ISBN 0-8153-3218-1.
- ^ Csiszar K (2001). "Lysyl oxidases: a novel multifunctional amine oxidase family". Prog. Nucleic Acid Res. Mol. Biol. 70: 1–32. doi:10.1016/S0079-6603(01)70012-8. PMID 11642359.
- ^ Siegel RC, Fu JC, Uto N, Horiuchi K, Fujimoto D (1982). "Collagen cross-linking: lysyl oxidase dependent synthesis of pyridinoline in vitro: confirmation that pyridinoline is derived from collagen". Biochem. Biophys. Res. Commun. 108 (4): 1546–50. doi:10.1016/S0006-291X(82)80083-1. PMID 6129847.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Dawson DA, Rinaldi AC, Pöch G (2002). "Biochemical and toxicological evaluation of agent-cofactor reactivity as a mechanism of action for osteolathyrism". Toxicology. 177 (2–3): 267–84. doi:10.1016/S0300-483X(02)00233-0. PMID 12135629.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Wilmarth KR, Froines JR (1992). "In vitro and in vivo inhibition of lysyl oxidase by aminopropionitriles". J Toxicol Environ Health. 37 (3): 411–23. doi:10.1080/15287399209531680. PMID 1359158.
{{cite journal}}: Unknown parameter|month=ignored (help) - ^ Erler JT, Bennewith KL, Nicolau M, Dornhöfer N, Kong C, Le QT, Chi JT, Jeffrey SS, Giaccia AJ (2006). "Lysyl oxidase is essential for hypoxia-induced metastasis". Nature. 440 (7088): 1222–6. doi:10.1038/nature04695. PMID 16642001.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Erler JT, Giaccia AJ (2006). "Lysyl oxidase mediates hypoxic control of metastasis". Cancer Res. 66 (21): 10238–41. doi:10.1158/0008-5472.CAN-06-3197. PMID 17079439.
{{cite journal}}: Unknown parameter|month=ignored (help) - ^ Erler JT, Bennewith KL, Cox TR, Lang G, Bird D, Koong A, Le QT, Giaccia AJ (2009). "Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche". Cancer Cell. 15 (1): 35–44. doi:10.1016/j.ccr.2008.11.012. PMC 3050620. PMID 19111879.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Rodríguez C, Rodríguez-Sinovas A, Martínez-González J (2008). "Lysyl oxidase as a potential therapeutic target". Drug News Perspect. 21 (4): 218–24. doi:10.1358/dnp.2008.21.4.1213351. PMID 18560621.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link)
Further reading
External links
- Lysyl+Oxidase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)