DPPIV inhibitors extend GLP-2 mediated tumour promoting effects on intestinal cancer cells K. Masur ⁎ , F Schwartz, F. Entschladen, B. Niggemann, K.S. Zaenker Institute of Immunology, Witten/Herdecke University, Stockumer Str. 10, 58448 Witten, Germany Received 1 March 2006; received in revised form 4 July 2006; accepted 6 July 2006 Available online 14 August 2006 Abstract Background: The glucagon-like peptides-1 and -2 (GLP-1 and -2) are co-secreted after food intake from intestinal L cells. Since both peptides are rapidly degraded by dipeptidyl peptidase-IV (DPPIV), research is focused on the development of DPPIV inhibitors or DPPIV resistant. Aims: In this study we investigated, whether the inhibition of DPPIV activity and the resulting increased half-life of DPPIV substrates may influence cancer development and progression. Methods: We examined proliferation and migratory activity of two human colon cancer cell lines (SW480, HT29) after stimulation with GLP-2 in combination with or without DPPIV inhibitors. Results: Migratory activity was increased by 25% from 20% matrix induced activity to a maximum of 45% (100 nM GLP-2). In cells expressing CD26, migration was prolonged by addition of DPPIV inhibitors in a concentration dependent manner. After treatment with GLP-2 doubling time decreased from 2.4 to 1.5 days — and addition of DPPIV inhibitors enhanced the effect of GLP-2. Conclusions: The use of DPPIV inhibitors together with GLP-2 led to increased proliferation as well as elevated migratory activity. Therefore, the use of DPPIV inhibitors could increase the risk of promoting an already existing intestinal tumour and may support the potential of colon cancer cells to metastasize. © 2006 Elsevier B.V. All rights reserved. Keywords: Glucagon-like peptide; Dipeptidyl peptidase-IV; Proliferation; Migration 1. Introduction Over the past few years increasing evidence was found in epidemiological studies that obese people, diabetic patients and/ or people with elevated glucose serum levels have a higher incidence of developing cancer at several organ sites, including colon [1]. In part, this elevated cancer risk may be explained by alterations in the metabolism of endogenous hormones (e.g. sex steroids, insulin, and insulin-like growth factors), which can lead to distortion of normal balance between cell proliferation, differentiation, and apoptosis [2]. The Glucagon-like peptide-2 (GLP-2) is an intestinal peptide hormone derived from the tissue-specific, post-translational processing of the proglucagon gene [3]. After nutritional intake, GLP-1 and GLP-2 are secreted from intestinal enteroendocrine L cells. While GLP-1 is leading to an increased secretion of insulin [4], GLP-2 causes increased intestinal hexose transport respectively [5]. Once released, GLP-2 regulates gastric motility, gastric acid secretion, intestinal hexose transport, increases crypt cell proliferation and regulates inhibition of apoptosis in the enterocyte and crypt compartments [6]. GLP-2 also enhances intestinal epithelial barrier function by affecting both para- cellular and transcellular pathways [7]. The signals of GLP-2 are mediated through the GLP-2 receptor (GLP-2R), a subclass B receptor of G protein-coupled receptors which is expressed in cells of the stomach, jejunum, ileum, and colon [8], but is also found in the brain [3]. The biological activities of GLP-1 and GLP-2 are regulated by the proteolytic cleavage of the first two N-terminal amino acids by dipeptidyl peptidase-IV (DPPIV) [9,10]. DPPIV – also known as CD26 – is a cell surface glycoprotein that serves in signal transduction and as a proteolytic enzyme [11]. First dis- covered in immune cells, CD26 functions as a co-stimulatory molecule in lymphocytes, where its expression is regulated upon the activation of the cells. In contrast, CD26 is constitutively Regulatory Peptides 137 (2006) 147 – 155 www.elsevier.com/locate/regpep ⁎ Corresponding author. Tel.: +49 2302 926178; fax: +49 2302 926158. E-mail address: kmasur@uni-wh.de (K. Masur). 0167-0115/$ - see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.regpep.2006.07.003