Background::Cholangiocarcinoma (CCA) has a poor prognosis and only limited palliative
treatment options. The deficiency of adiponectin and adenosine monophosphate-activated protein kinase
(AMPK) signaling was reported in several malignancies, but the alteration of these proteins in CCA is
still unclear.Objectives:::This study aimed to assess the role of adiponectin and AMPK signaling in CCA. Furthermore,
AdipoRon, a novel adiponectin receptor (AdipoR) agonist, was evaluated in vitro and in vivo as a
new anti-tumor therapy for CCA.Methods::The expression of AdipoR1 and p-AMPKα in human tissue microarrays (TMAs) was evaluated
by immunohistochemistry staining (IHC). The effect of 2-(4-Benzoylphenoxy)-N-[1-(phenylmethyl)-
4-piperidinyl]-acetamide (AdipoRon) was investigated in vitro with proliferation, crystal violet,
migration, invasion, colony formation, senescence, cell cycle and apoptosis assays and in vivo using a
CCA engineered mouse model (AlbCre/LSL-KRASG12D/p53L/L). RT-qPCR and western blot methods
were applied to study molecular alterations in murine tissues.Results::AdipoR1 and p-AMPKα were impaired in human CCA tissues, compared to adjacent non-tumor
tissue. There was a positive correlation between the AdipoR1 and p-AMPKα levels in CCA tissues.
Treatment with AdipoRon inhibited proliferation, migration, invasion and colony formation and induced
apoptosis in a time- and dose-dependent manner in vitro(p<0.05). In addition, AdipoRon reduced
the number of CCA and tumor volume, prolonged survival, and decreased metastasis and ascites in the
treated group compared to the control group (p<0.05).Conclusions::AdipoR1 and p-AMPKα are impaired in CCA tissues, and AdipoRon effectively inhibits
CCA in vitro and in vivo. Thus, AdipoRon may be considered as a potential anti-tumor therapy in CCA.