Inhibition of the apelin/apelin receptor axis decreases cholangiocarcinoma growth

Cancer Lett. 2017 Feb 1:386:179-188. doi: 10.1016/j.canlet.2016.11.025. Epub 2016 Nov 26.

Abstract

Purpose: Cholangiocarcinoma (CCA) is a malignancy of the biliary epithelium that is associated with low five-year survival. The apelin receptor (APLNR), which is activated by the apelin peptide, has not been studied in CCA. The purpose of this study is to determine if inhibition of the apelin/APLNR axis can inhibit CCA growth.

Methods: Immunohistochemistry, rtPCR, immunofluorescence, flow cytometry, and ELISA was used to measure APLNR expression in human CCA cells and tissues. Mz-ChA-1 cells were treated with increasing concentrations of apelin and ML221, an APLNR antagonist. Expression of proliferative and angiogenic genes were measured via rtPCR. In vivo, Mz-ChA-1 cells were injected into the flanks of nu/nu mice, which were treated with ML221 (150 μg/kg) via tail vein injection.

Results: Expression of the apelin/APLNR axis was increased in CCA. In vitro, CCA proliferation and angiogenesis was inhibited by ML221 treatment. ML221 treatment significantly decreased tumor growth in nu/nu mice.

Conclusion: The apelin/APLNR axis regulates CCA proliferation and angiogenesis. Inhibition of the apelin/APLNR axis decreases tumor growth in our xenograft model. Targeting APLNR signaling has the potential to serve as a novel, tumor directed therapy for CCA.

Keywords: Apelin; Apelin receptor; Biliary epithelium; Cholangiocarcinoma; Proliferation.

MeSH terms

  • Adult
  • Aged, 80 and over
  • Angiogenesis Inhibitors / pharmacology*
  • Animals
  • Apelin
  • Apelin Receptors
  • Bile Duct Neoplasms / drug therapy*
  • Bile Duct Neoplasms / genetics
  • Bile Duct Neoplasms / metabolism
  • Bile Duct Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects*
  • Cholangiocarcinoma / drug therapy*
  • Cholangiocarcinoma / genetics
  • Cholangiocarcinoma / metabolism
  • Cholangiocarcinoma / pathology
  • Female
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Male
  • Mice, Inbred BALB C
  • Mice, Nude
  • Middle Aged
  • Neoplasm Invasiveness
  • Neovascularization, Pathologic*
  • Nitrobenzoates / pharmacology*
  • Pyrans / pharmacology*
  • Receptors, G-Protein-Coupled / antagonists & inhibitors*
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism
  • Signal Transduction / drug effects
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • 4-oxo-6-((pyrimidin-2-ylthio)methyl)-4H-pyran-3-yl 4-nitrobenzoate
  • APLN protein, human
  • APLNR protein, human
  • Angiogenesis Inhibitors
  • Apelin
  • Apelin Receptors
  • Intercellular Signaling Peptides and Proteins
  • Nitrobenzoates
  • Pyrans
  • Receptors, G-Protein-Coupled