SFEBES2014 Oral Communications Endocrine regulation of cell behaviour (6 abstracts)
Inhibition of human NET cell proliferation by a peptide identified through phage display screening
Mark Stevenson 1 , Kate Lines 1 , Lykourgos-Panagiotis Zalmas 1 , Mahsa Javid 1 , Juris Galvanovskis 1 , Simona Grozinsky-Glasberg 2 , Matthew Wood 1 , Ashley Grossman 1 & Rajesh Thakker 1
1University of Oxford, Oxford, UK; 2Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Neuroendocrine tumours (NETs) occur in multiple sites including, the pancreas, gastrointestinal tract, lung, thymus, parathyroid, adrenals and pituitary. Current treatments for advanced NETs such as surgery, chemotherapy or radiotherapy, rarely achieve a cure due to metastases at presentation therefore additional therapeutic treatments are required. Identification of cell surface receptors or binding sites that are unique or up-regulated on tumour or neuroendocrine tissue could lead to novel targeted drugs, radio-isotope or gene therapy treatments. To identify ligands to such receptors we used a phage display selection technique in which a library of peptides is expressed on the outside of phage virions, with each virion displaying a unique peptide encoded by the genetic material inside. Three rounds of phage display screening using a 12-mer library (New England BioLabs) to three human neuroendocrine (carcinoid) cell lines, BON-1, H727 and H720, which were shown to express chromogranin A, neuron specific enolase and menin, was performed and binding phage identified. A lead candidate peptide ALWPPNLHAWVP emerged since it was recovered in 81% of BON-1 cell binding clones and 73% of H727 cell binding clones, with the frequency of ALWPPNLHAWVP-bearing phage increasing from the second to the third round, confirming that this peptide was enriched during screening. Incubation of BON-1 cells with biotinylated ALWPPNLHAWVP peptide or a scrambled peptide control followed by FITC–avidin and confocal microscopic analysis confirmed the ability of the peptide to bind to these cells. Application of 10 μM ALWPPNLHAWVP mediated a 70% decrease (P<0.005) in BON-1 and 35% decrease (P<0.05) in H727 cell proliferation after 6 days, compared to the scrambled control peptide. This was in part mediated by a 1.23-fold (P<0.02) increase in apoptosis, without an increase in cell senescence. Thus, our studies have identified a peptide that may play a role in targeting NET cells and in reducing NET tumour growth.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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