LOX propeptide: A novel peptide cancer therapeutic

Fri, 10/04/2013 - 12:04

Lysyl oxidase, also known as LOX, is a copper-dependent enzyme that cross-links collagen and elastin through the oxidative deamination of peptidyl lysine (collagen and elastin) and hydroxylysine (collagen only) residues, thereby playing a critical role in maintaining the structural integrity of the extracellular matrix (1).

There are five proteins in the LOX family, LOX itself and four LOX-like proteins (LOXL1-4). These share a highly conserved C-terminus, which encodes the enzyme domain, and an N-terminal region that shows greater variation between different family members and encodes a propeptide (2). LOX is highly expressed in tissues that contain collagen or elastin fibres, which include skin, lung, cartilage and the cardiovascular system, and is secreted as a 50kDa pro-enzyme that is subsequently cleaved to give rise to the functional 32kDa LOX enzyme, and the 18kDa LOX propeptide.

LOX is considered to be a potential therapeutic target for the prevention of metastases, however the cancer biology of LOX is extremely complex since its expression is associated with both tumour progression and tumour suppression.  LOX expression is known to be regulated by Hypoxia Inducible Factor (HIF) and is elevated in the hypoxic tumour micro-environment. Increased LOX expression is associated with tumour cell metastasis and poor survival rates (3); inhibition of the expression or the enzymatic activity of LOX has been shown to reduce tumour growth and metastasis in various cancer models (4).

The tumour suppressor activity of LOX is attributed to the LOX propeptide, which has been identified as an inhibitor of Ras signalling. Palamakumbura et al demonstrated the role of the LOX propeptide in the inhibition of Ras-dependent transformation of fibroblasts, by measuring changes in cell proliferation and growth in soft agar (5). This group co-transfected Ras-transformed NIH3T3 cells with a GFP-PDK1 construct and a LOX propeptide expression vector, and illustrated that Ras-induced membrane localisation of PDK1 was inhibited by the LOX propeptide. Seiichi et al have used LOX propeptide antibodies to show that the LOX propeptide interacts with HSP70, levels of which are elevated in many cancers, subsequently compromising HSP70 functions that are essential for tumour cell growth and survival (6).

The Ras/Raf/MEK/ERK cascade has been implicated in proliferation, differentiation, apoptosis and migration, and these kinases are therefore seen as attractive targets for the development of cancer therapeutics. Mutations in the Ras oncogene have been implicated in 30% of all human cancers, including 50% of colon cancers and 90% of pancreatic cancers and, since it is capable of inhibiting Ras-induced effects, the LOX propeptide is currently being investigated as a novel peptide cancer therapeutic.

  1. PMID: 22767499
  2. PMID: 22453058
  3. PMID: 16642001
  4. PMID: 19111879
  5. PMID: 15277520
  6. PMID: 21536655

Novus Biologicals offers various LOX propeptide reagents for your research needs including:

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