Adiponectin promotes pancreatic cancer progression by inhibiting apoptosis via the activation of AMPK/Sirt1/PGC-1α signaling

// Bingqing Huang 1,2,* , Xixi Cheng 1,* , Dan Wang 1,* , Meiyu Peng 1 , Zhenyi Xue 1 , Yurong Da 1 , Ning Zhang 1 , Zhi Yao 2 , Min Li 3 , Aimin Xu 4 , and Rongxin Zhang 1,2 1 Research Center of Basic Medical Science, Tianjin Medical University, Tianjin, China. 2 Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Department of Immunology, Basic Medical College, Tianjin Medical University, Tianjin, China. 3 Department of Integrative Biology & Pharmacology, The University of Texas Medical School at Houston, Houston, TX, USA. 4 State Key laboratory of Pharmaceutical Biotechnology, and Department of Medicine, University of Hong Kong, Hong Kong, China. * These authors contributed equally to this work Correspondence: Rongxin Zhang, email: // Keywords : Adiponectin, AMPK, Sirt1, PGC1α, Apoptosis, Pancreatic cancer Received : March 14, 2014 Accepted : May 12, 2014 Published : May 13, 2014 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.