Abstract
Adiponectin is an adipocyte-secreted adipokine with pleiotropic actions. Clinical evidence has shown that serum adiponectin levels are increased and that adiponectin can protect pancreatic beta cells against apoptosis, which suggests that adiponectin may play an anti-apoptotic role in pancreatic cancer (PC). Here, we investigated the effects of adiponectin on PC development and elucidated the underlying molecular mechanisms. Adiponectin deficiency markedly attenuated pancreatic tumorigenesis in vivo. We found that adiponectin significantly inhibited the apoptosis of both human and mouse pancreatic cancer cells via adipoR1, but not adipoR2. Furthermore, adiponectin can increase AMP-activated protein kinase (AMPK) phosphorylation and NAD-dependent deacetylase sirtuin-1 (Sirt1) of PC cells. Knockdown of AMPK or Sirt1 can increase the apoptosis in PC cells. AMPK up-regulated Sirt1, and Sirt1 can inversely phosphorylate AMPK. Further studies have shown that Sirt1 can deacetylate peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), which can increase the expression levels of mitochondrial genes. Thus, adiponectin exerts potent anti-apoptotic effects on PC cells via the activation of AMPK/Sirt1/PGC1α signaling. Finally, adiponectin can elevate β-catenin levels. Taken together, these novel findings reveal an unconventional role of adiponectin in promoting pancreatic cancers, and suggest that the effects of adiponectin on tumorigenesis are highly tissue-dependent.
Highlights
Pancreatic cancer, which is a gastrointestinal malignancy with increasing incidence and mortality rates, exhibits dismal prognosis and no effective treatment, with a 5-year survival rate of less than 5%
Our in vivo studies showed that adiponectin deficiency could significantly alleviate pancreatic cancer growth and metastasis, suggesting that there is an unconventional role of adiponectin in the promotion of pancreatic cancer progression
Further experiments showed that adiponectin inhibited the apoptosis of pancreatic cancer cells via AdipoR1, which was consistent with the effect on myocytes
Summary
Pancreatic cancer, which is a gastrointestinal malignancy with increasing incidence and mortality rates, exhibits dismal prognosis and no effective treatment, with a 5-year survival rate of less than 5%. Many case-control and prospective studies have www.impactjournals.com/oncotarget shown that the serum concentration of adiponectin is decreased in breast cancer, hepatocellular carcinoma (HCC) and colorectal cancer [6,7,8]. Many other studies found higher serum adiponectin levels or a higher adiponectin/leptin ratio in pancreatic cancer patients who exhibited a positive or strong positive expression of AdipoR1 and AdipoR2 and that this higher level correlated strongly with the proinflammatory cytokine IL-6 [2, 12,13,14]. Adiponectin can protect against pancreatic beta cell apoptosis by the induction of Erk and Akt phosphorylation [15]. Taken together, these foundings suggested that adiponectin may play an anti-apoptotic role in pancreatic cancer, and requires further exploration
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