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.

Molecular function of α7 nicotinic receptors as drug targets

“…; Zhao, ; Pepper et al . ). Thus, interference with α7 protein expression or treatment with specific inhibitors can reverse proangiogenic effects of nicotine and inhibit cancer cell growth (Wu et al .…”

“…; Pepper et al . ). Thus, selective antagonists or NAMs that could specifically target the overexpressed α7 would be good candidate drugs.…”

Cancer and neurodegeneration: two sides, same coin?

“…Two papers just published would at first glance have little in common: one features a novel approach to combating metastases [1] whilst the other suggests a new strategy for treating Alzheimer's, [2]. Nonetheless, here we describe a possible link based on the concept that both cancer and neurodegeneration are inappropriately activated forms of development, and in both cases could be mediated by the same bioactive peptide acting at the same receptor.…”

“…Interestingly enough, a similar signalling system could be operational in metastases: studies with breast cancer cell lines have shown an enhancement of metastatic cell activity in response to peptide treatment, in a calcium and α7-nAChR dependent manner [5]. Most recently we have demonstrated that AChE-pept ide could indeed play a pivotal role in cell migration, with its action blocked by interception at the level of the α7-nAChR [1]. …”

“…Hence this form of inter-cellular communication would not be restricted to nervous system signalling and as such could represent a very basic system for triggering calcium entry into a wide range of cells for promoting growth, that would have the further advantage of allowing interfacing between the very distinct control systems (nervous, endocrine and immune). The problem, as illustrated both for metastases [1] and for neurodegeneration [2] would be when it is activated inappropriately.…”