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Novel Adiponectin Receptor Agonist Inhibits Cholangiocarcinoma via Adenosine Monophosphate-activated Protein Kinase

Khac Cuong Bui1,2,3,4, Thi Mai Ly Nguyen1,4,5, Samarpita Barat1

  • 1Department of Internal Medicine I, Universitätsklinikum Tübingen, Tübingen, Germany.

Current Medicinal Chemistry
|February 16, 2024
PubMed
Abstract

Insights

Adiponectin receptor 1 (AdipoR1) and AMPK signaling are diminished in cholangiocarcinoma (CCA). The AdipoRon drug effectively suppressed CCA growth and metastasis in preclinical studies, indicating its potential as a novel cancer therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Cholangiocarcinoma (CCA) presents a poor prognosis with limited treatment options.
  • Adiponectin and AMPK signaling pathways are implicated in various cancers, but their role in CCA remains largely uncharacterized.
  • Investigating these pathways is crucial for developing new therapeutic strategies for CCA.

Purpose of the Study:

  • To determine the expression levels of AdipoR1 and phosphorylated AMPK (p-AMPKα) in human CCA tissues.
  • To evaluate the anti-tumor efficacy of AdipoRon, a novel AdipoR agonist, in both in vitro and in vivo CCA models.
  • To explore AdipoRon's potential as a therapeutic agent for CCA.

Main Methods:

  • Immunohistochemistry (IHC) was used to assess AdipoR1 and p-AMPKα expression in human CCA tissue microarrays (TMAs).
  • In vitro assays (proliferation, migration, invasion, colony formation, apoptosis, cell cycle, senescence) were performed to evaluate AdipoRon's effects.
  • An engineered mouse model of CCA (AlbCre/LSL-KRASG12D/p53L/L) was utilized for in vivo studies, with molecular analyses using RT-qPCR and western blot.

Main Results:

  • AdipoR1 and p-AMPKα expression were significantly reduced in human CCA tissues compared to adjacent non-tumor tissues.
  • A positive correlation was observed between AdipoR1 and p-AMPKα levels in CCA.
  • AdipoRon demonstrated significant inhibition of CCA cell proliferation, migration, invasion, and colony formation in vitro, while inducing apoptosis.
  • In vivo, AdipoRon treatment led to reduced tumor volume, decreased metastasis and ascites, prolonged survival, and suppressed CCA progression in the mouse model.

Conclusions:

  • AdipoR1 and p-AMPKα signaling pathways are impaired in CCA.
  • AdipoRon exhibits potent anti-tumor activity against CCA both in vitro and in vivo.
  • AdipoRon represents a promising therapeutic candidate for the treatment of cholangiocarcinoma.
Keywords:
AdipoR agonistadipoRonadiponectincholangiocarcinomamurine tissues.therapy

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