VIP and PACAP analogs regulate therapeutic targets in high-risk neuroblastoma cells

Peptides. 2016 Apr:78:30-41. doi: 10.1016/j.peptides.2016.01.014. Epub 2016 Jan 27.

Abstract

Neuroblastoma (NB) is a pediatric cancer. New therapies for high-risk NB aim to induce cell differentiation and to inhibit MYCN and ALK signaling in NB. The vasoactive intestinal peptide (VIP) and the pituitary adenylate cyclase-activating polypeptide (PACAP) are 2 related neuropeptides sharing common receptors. The level of VIP increases with NB differentiation. Here, the effects of VIP and PACAP analogs developed for therapeutic use were studied in MYCN-amplified NB SK-N-DZ and IMR-32 cells and in Kelly cells that in addition present the F1174L ALK mutation. As previously reported by our group in IMR-32 cells, VIP induced neuritogenesis in SK-N-DZ and Kelly cells and reduced MYCN expression in Kelly but not in SK-N-DZ cells. VIP decreased AKT activity in the ALK-mutated Kelly cells. These effects were PKA-dependent. IMR-32, SK-NDZ and Kelly cells expressed the genes encoding the 3 subtypes of VIP and PACAP receptors, VPAC1, VPAC2 and PAC1. In parallel to its effect on MYCN expression, VIP inhibited invasion in IMR-32 and Kelly cells. Among the 3 PACAP analogs tested, [Hyp(2)]PACAP-27 showed higher efficiency than VIP in Kelly cells. These results indicate that VIP and PACAP analogs act on molecular and cellular processes that could reduce aggressiveness of high-risk NB.

Keywords: AKT; ALK; Differentiation; Invasion; MYCN; PKA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anaplastic Lymphoma Kinase
  • Cell Differentiation / drug effects*
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cyclic AMP-Dependent Protein Kinases / genetics
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Mutation
  • N-Myc Proto-Oncogene Protein / genetics
  • N-Myc Proto-Oncogene Protein / metabolism
  • Neurons / drug effects*
  • Neurons / metabolism
  • Neurons / pathology
  • Organ Specificity
  • Pituitary Adenylate Cyclase-Activating Polypeptide / chemical synthesis
  • Pituitary Adenylate Cyclase-Activating Polypeptide / pharmacology*
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I / genetics
  • Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I / metabolism
  • Receptors, Vasoactive Intestinal Peptide, Type II / genetics
  • Receptors, Vasoactive Intestinal Peptide, Type II / metabolism
  • Receptors, Vasoactive Intestinal Polypeptide, Type I / genetics
  • Receptors, Vasoactive Intestinal Polypeptide, Type I / metabolism
  • Signal Transduction
  • Structure-Activity Relationship
  • Vasoactive Intestinal Peptide / chemical synthesis
  • Vasoactive Intestinal Peptide / pharmacology*

Substances

  • ADCYAP1 protein, human
  • MYCN protein, human
  • N-Myc Proto-Oncogene Protein
  • Pituitary Adenylate Cyclase-Activating Polypeptide
  • Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I
  • Receptors, Vasoactive Intestinal Peptide, Type II
  • Receptors, Vasoactive Intestinal Polypeptide, Type I
  • Vasoactive Intestinal Peptide
  • ALK protein, human
  • Anaplastic Lymphoma Kinase
  • Receptor Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins c-akt
  • Cyclic AMP-Dependent Protein Kinases