title: Tumor cell migration is inhibited by a novel therapeutic strategy antagonizing the alpha-7 receptor.
abstract: A 14mer peptide (T14) derived from the C-terminus of acetylcholinesterase (AChE) selectively activates metastatic breast cancer cells via the alpha-7 nicotinic receptor (α7 nAChR). This naturally occurring peptide is also present in brain, is elevated in Alzheimer's disease, and is antagonised by a cyclized variant (NBP-14). Here we investigated the effects of NBP-14 in six different cancer cell lines, primary leukemia B-cells and normal B-cells. All cells tested expressed α7 nAChR, intracellular and extracellular T14. However, NBP-14 showed low toxicity and weak anti-proliferative effects in the majority of the cell lines and was even less toxic in normal B-cells when compared to primary chronic lymphocytic leukemia cells (P < 0.001). Given the potential role of T14 peptide in metastasis, we next investigated the effects of NBP-14 on tumor cell migration, where it caused a dose-dependent reduction. The extent of NBP-14 inhibition positively correlated with the migration of the cells (r2 = 0.45; P = 0.06). Furthermore, NBP-14 preferentially inhibited the migration of primary leukemia cells when compared with normal B-cells (P = 0.0002); when the normal B-cell data was excluded, this correlation was strengthened (r2 = 0.80; P = 0.006). Importantly, the constitutive α7 nAChR expression positively correlated with intracellular T14 levels (r2 = 0.91; P = 0.0003) and inversely correlated with extracellular T14 levels in the cell culture supernatants (r2 = -0.79; P = 0.034). However, in the presence of NBP-14, α7 nAChR expression was reduced (P = 0.04) and the most migratory cells showed the largest reduction in expression. In conclusion, NBP-14-mediated antagonism of the α7 nAChR offers a novel therapeutic strategy with the potential to inhibit tumor cell migration.
authors.affiliation: Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, CF14 4XN, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Pepper
authors.affiliation: Neuro-Bio Ltd, Culham Science Centre, Abingdon, OX14 3DB, UK.
authors.forename: Henry
authors.initials: H
authors.lastname: Tu
authors.affiliation: Neuro-Bio Ltd, Culham Science Centre, Abingdon, OX14 3DB, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Morrill
authors.affiliation: Neuro-Bio Ltd, Culham Science Centre, Abingdon, OX14 3DB, UK.
authors.forename: Sara
authors.initials: S
authors.lastname: Garcia-Rates
authors.affiliation: Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, CF14 4XN, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Fegan
authors.affiliation: Neuro-Bio Ltd, Culham Science Centre, Abingdon, OX14 3DB, UK.
authors.forename: Susan
authors.initials: S
authors.lastname: Greenfield
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D009361:Neoplasm Invasiveness; D010456:Peptides, Cyclic / Q000494:pharmacology*; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000037:antagonists & inhibitors*
chemical_list: D016229:Amyloid beta-Peptides; C000620618:NBP14 peptide; D010456:Peptides, Cyclic; D064569:alpha7 Nicotinic Acetylcholine Receptor
keywords: acetylcholinesterase peptide; alpha-7 receptor; cell migration; cyclized variant; metastases