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

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.

(Ir)relevance of Metformin Treatment in Patients with Metastatic Pancreatic Cancer: An Open-Label, Randomized Phase II Trial

“…In our study, adiponectin level resulted in an independent predictor both for death and disease progression. This is in agreement with recent in vivo studies (48) showing that, unlike most other cancers, adiponectin deficiency significantly alleviate pancreatic cancer growth and metastasis. This unconventional role of adiponectin in the promotion of pancreatic cancer progression could be explained by its potent antiapoptotic effects via the activation of AMPK/Sirt1/PGC1a signaling (48).…”

Adiponectin Regulates the Development and Progression of MCA-Induced Sarcoma in Mice

“…Besides, the mortality rates of the adiponectin-deficient mice with sarcomas were lower than the rates of the WT control mice ( Figure 2B). These results were consistent to our previous findings that adiponectin deficiency suppressed pancreatic cancer [7]. In spite of this, the exact roles of adiponectin in cancers are controversial and need further study.…”

“…Many reports demonstrated that adiponectin has regulatory effects on the development and progression of various tumors via different signaling pathways [4][5][6]. Our previous studies also explore the potential mechanism of adiponectin on pancreatic cancer [7]. However, the roles of adiponectin in sarcomas remain largely unknown.…”

Prediagnostic plasma adiponectin and survival among patients with colorectal cancer.

“…Furthermore, a study conducted in adiponectin transgenic mice showed that elevated levels of adiponectin do not protect against CRC development (46). Third, emerging evidence has demonstrated that adiponectin exerts potent anti-apoptotic effect via activation of the AMPK/Sirtuin 1 (SIRT1)/PGC-1α pathway, leading to increased mitochondrial gene expression and cell proliferation (19). Lastly, adiponectin has been associated with a lower risk of development of fatty liver (47).…”