The Role And Mechanism Of Adiponectin In The Progression Of Pancreatic Cancer

BACKGROUND & AIMS: Adiponectin(APN) is an adipocyte-secreted adipokine with insulin-sensitizing, anti-diabetes, and anti-inflammatory. It has been reported that adiponectin has anti-tumor effects in liver cancer, breast cancer, prostate cancer and other cancers, but its role in pancreatic cancer is not clear. Here, we first investigated the effects of adiponectin on Pancreatic cancer(PC) development and elucidated the underlying molecular mechanisms.METHODS: Orthotopic and ectopic PC tumor model were built in APN knockout(KO) mice and their wild-type(WT) littermates. We collected tumor tissues, and analyzed the tumor sizes and weights, pathology, and molecular between APN KO and WT mice by histologic and immunohistochemistry analyses, immunoblot, and quantitative polymerase chain reaction. We treated human and mouse pancreatic cancer cell lines with exogenous adiponectin protein, and detected the apoptosis and proliferation.RESULTS: Adiponectin deficiency markedly attenuates pancreatic tumorigenesis of H7 and Panc02 cells. Exogenous adiponectin significantly inhibits the apoptosis of both human and mouse pancreatic cancer cells. Adiponectin activates AMP-activated protein kinase(AMPK), NAD-dependent deacetylase sirtuin-1(Sirt1), and peroxisome proliferator-activated receptor gamma coactivator 1-alpha(PGC1α) via its receptor Adipo R1. Elevated Sirt1 can deacetylate PGC1α, and deacetylated PGC1α increases the expression levels of mitochondrial genes and reprograms the metabolism of pancreatic cancer cells. Adiponectin protects the functional integrity of the mitochondrial membrane, and thereby exerts potent anti-apoptotic effects by PGC1α/caspase 3. In H7 cells, adiponectin has no effect on the canonical AKT/GSK3β signaling but increases the levels of β-catenin and cyclin D1.CONCLUSIONS: These novel findings reveal an unconventional role of adiponectin in promoting pancreatic cancers, and highlight differential effects of this adipokine in the pathogenesis of different tumors.