Oncotarget

Research Papers:

Tumor cell migration is inhibited by a novel therapeutic strategy antagonizing the alpha-7 receptor

Chris Pepper, Henry Tu, Paul Morrill, Sara Garcia-Rates, Chris Fegan and Susan Greenfield _

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Oncotarget. 2017; 8:11414-11424. https://doi.org/10.18632/oncotarget.14545

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Abstract

Chris Pepper1, Henry Tu2, Paul Morrill2, Sara Garcia-Rates2, Chris Fegan1, Susan Greenfield2

1Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, CF14 4XN, UK

2Neuro-Bio Ltd, Culham Science Centre, Abingdon, OX14 3DB, UK

Correspondence to:

Susan Greenfield, email: [email protected]

Keywords: alpha-7 receptor, acetylcholinesterase peptide, cyclized variant, metastases, cell migration

Received: July 06, 2016     Accepted: December 26, 2016     Published: January 06, 2017

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.


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