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.

Incretin‐based therapies and risk of pancreatic cancer in patients with type 2 diabetes: A meta‐analysis of randomized controlled trials

“…In agreement with our previous findings, it has been shown that GLP‐1 receptor agonist exendin‐4 can inhibit cell growth in colon cancer cells and breast cancer cells in vitro and in vivo. Furthermore, exendin‐4 also counteracts the invasive potential of human neuroblastoma cells . These consistent results from clinical and laboratory studies suggest that long‐term incretin‐based therapies might shed some light on how to prevent the development and progression of pancreatic malignancy, which usually has a poor outcome.…”

“…Furthermore, exendin-4 also counteracts the invasive potential of human neuroblastoma cells. 64 These consistent results from clinical and laboratory studies suggest that long-term incretinbased therapies might shed some light on how to prevent the development and progression of pancreatic malignancy, which usually has a poor outcome.…”

Inhibition of hypoxia inducible factors combined with all-trans retinoic acid treatment enhances glial transdifferentiation of neuroblastoma cells

“…Similarly for the SKNBE2c shHIF1A (45 ± 8.4 colonies) and shEPAS1 (38.5 ± 0.7 colonies) cells compared to the SKNBE2c shCTR cells (71 ± 2.8 colonies). The SKNAS cells showed weaker growth than the SHSY5Y and SKNBE2c cells 29 , and this depletion of the HIF1A / EPAS1 genes did not change their growth (data not shown).…”

The Neurotrophic Function of Glucagon-Like Peptide-1 Promotes Human Neuroblastoma Differentiation via the PI3K-AKT Axis

“…Earlier studies have demonstrated that agonists of GLP-1Rs induce neurite outgrowth of pheochromocytoma (PC12) cells [26,40] and human neuroblastoma cells (SH-SY5Y) [32,39]. Each study has grown and differentiated cells in different medium conditions, but all studies differentiated cells in low serum medium, such as 2% FBS [34,41], 0.5% FBS [26], or 1% FBS and 2% horse serum [40]. This study consolidated previous cell-culture protocols, ensuring that the 5-day RA-conditioned SH-SY5Y cells were subcultured in polyethylenimine (PEI) coated dishes with GLP-1 contained Neurobasal and B27 supplement.…”