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Exendin-4 induces cell adhesion and differentiation and counteracts the invasive potential of human neuroblastoma cells.

ABSTRACT: Exendin-4 is a molecule currently used, in its synthetic form exenatide, for the treatment of type 2 diabetes mellitus. Exendin-4 binds and activates the Glucagon-Like Peptide-1 Receptor (GLP-1R), thus inducing insulin release. More recently, additional biological properties have been associated to molecules that belong to the GLP-1 family. For instance, Peptide YY and Vasoactive Intestinal Peptide have been found to affect cell adhesion and migration and our previous data have shown a considerable actin cytoskeleton rearrangement after exendin-4 treatment. However, no data are currently available on the effects of exendin-4 on tumor cell motility. The aim of this study was to investigate the effects of this molecule on cell adhesion, differentiation and migration in two neuroblastoma cell lines, SH-SY5Y and SK-N-AS. We first demonstrated, by Extra Cellular Matrix cell adhesion arrays, that exendin-4 increased cell adhesion, in particular on a vitronectin substrate. Subsequently, we found that this molecule induced a more differentiated phenotype, as assessed by i) the evaluation of neurite-like protrusions in 3D cell cultures, ii) the analysis of the expression of neuronal markers and iii) electrophysiological studies. Furthermore, we demonstrated that exendin-4 reduced cell migration and counteracted anchorage-independent growth in neuroblastoma cells. Overall, these data indicate for the first time that exendin-4 may have anti-tumoral properties.

SUBMITTER: Luciani P

PROVIDER: S-EPMC3750033 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Exendin-4 induces cell adhesion and differentiation and counteracts the invasive potential of human neuroblastoma cells.

Luciani Paola P Deledda Cristiana C Benvenuti Susanna S Squecco Roberta R Cellai Ilaria I Fibbi Benedetta B Marone Ilaria Maddalena IM Giuliani Corinna C Modi Giulia G Francini Fabio F Vannelli Gabriella Barbara GB Peri Alessandro A

PloS one 20130822 8

Exendin-4 is a molecule currently used, in its synthetic form exenatide, for the treatment of type 2 diabetes mellitus. Exendin-4 binds and activates the Glucagon-Like Peptide-1 Receptor (GLP-1R), thus inducing insulin release. More recently, additional biological properties have been associated to molecules that belong to the GLP-1 family. For instance, Peptide YY and Vasoactive Intestinal Peptide have been found to affect cell adhesion and migration and our previous data have shown a considera ...[more]

PMID: 23990978

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Project description:BackgroundAlzheimer's disease (AD) is characterized by neurodegeneration and changes in cellular processes, including neurogenesis. Proteolytic processing of the amyloid precursor protein (APP) plays a central role in AD. Owing to varying APP processing, several beta-amyloid peptides (Abeta) are generated. In contrast to the form with 40 amino acids (Abeta40), the variant with 42 amino acids (Abeta42) is thought to be the pathogenic form triggering the pathological cascade in AD. While total-Abeta effects have been studied extensively, little is known about specific genome-wide effects triggered by Abeta42 or Abeta40 derived from their direct precursor C99.MethodsA combined transcriptomics/proteomics analysis was performed to measure the effects of intracellularly generated Abeta peptides in human neuroblastoma cells. Data was validated by real-time polymerase chain reaction (real-time PCR) and a functional validation was carried out using RNA interference.ResultsHere we studied the transcriptomic and proteomic responses to increased or decreased Abeta42 and Abeta40 levels generated in human neuroblastoma cells. Genome-wide expression profiles (Affymetrix) and proteomic approaches were combined to analyze the cellular response to the changed Abeta42- and Abeta40-levels. The cells responded to this challenge with significant changes in their expression pattern. We identified several dysregulated genes and proteins, but only the cellular retinoic acid binding protein 1 (CRABP1) was up-regulated exclusively in cells expressing an increased Abeta42/Abeta40 ratio. This consequently reduced all-trans retinoic acid (RA)-induced differentiation, validated by CRABP1 knock down, which led to recovery of the cellular response to RA treatment and cellular sprouting under physiological RA concentrations. Importantly, this effect was specific to the AD typical increase in the Abeta42/Abeta40 ratio, whereas a decreased ratio did not result in up-regulation of CRABP1.ConclusionWe conclude that increasing the Abeta42/Abeta40 ratio up-regulates CRABP1, which in turn reduces the differentiation potential of the human neuroblastoma cell line SH-SY5Y, but increases cell proliferation. This work might contribute to the better understanding of AD neurogenesis, currently a controversial topic.

Dataset Information

Exendin-4 induces cell adhesion and differentiation and counteracts the invasive potential of human neuroblastoma cells.

Publications

Exendin-4 induces cell adhesion and differentiation and counteracts the invasive potential of human neuroblastoma cells.

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