Adiponectin-activated AMPK stimulates dephosphorylation of AKT through protein phosphatase 2A activation.
ABSTRACT Low serum levels of adiponectin are a high risk factor for various types of cancer. Although adiponectin inhibits proliferation and metastasis of breast cancer cells, the underlying molecular mechanisms remain obscure. In this study, we show that adiponectin-activated AMPK reduces the invasiveness of MDA-MB-231 cells by stimulating dephosphorylation of AKT by increasing protein phosphatase 2A (PP2A) activity. Among the various regulatory B56 subunits, B56gamma was directly phosphorylated by AMPK at Ser(298) and Ser(336), leading to an increase of PP2A activity through dephosphorylation of PP2Ac at Tyr(307). We also show that both the blood levels of adiponectin and the tissue levels of PP2A activity were decreased in breast cancer patients and that the direct administration of adiponectin into tumor tissues stimulates PP2A activity. Taken together, these findings show that adiponectin, derived from adipocytes, negatively regulates the invasiveness of breast cancer cells by activating the tumor suppressor PP2A.
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ABSTRACT: In this study, we investigated the ability of luteolin, a plant derived flavonoid on hepatocarcinoma cell growth using HepG2 cell culture system. We found that luteolin increased the Smac/DIABLO releases, a mitochondrial protein that potentiates apoptosis. Luteolin also induced either transcriptional activity or expression of PPAR-gamma, a target of cancer growth that PPAR-gamma agonist sensitizes to apoptosis in certain cancer types. To find the possible upstream target molecules of PPAR-gamma activated by luteolin treatment, we used compound C, a specific inhibitor of AMP-activated protein kinase. Pre-treatment of Compound C significantly restored the activation or expression of PPAR-gamma stimulated by luteolin. This result indicated that AMPK signaling might be involved in the activation or expression of PPAR-gamma signaling pathway stimulated by luteolin. Moreover, we also found that luteolin inhibited the insulin-stimulated Akt phosphorylation as well as AICAR, a specific AMPK activator. These results propose that luteolin significantly induces cancer cell death through modulating survival signal pathways such as PPAR-gamma and Akt. AMPK signaling pathway may be an upstream regulator for survival signal pathways such as PPAR-gamma and Akt stimulated by luteolin.KSBB Journal. 01/2010; 25(6).
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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.Oncotarget 05/2014; · 6.63 Impact Factor
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ABSTRACT: Obesity increases the risk of developing multiple myeloma (MM). Adiponectin is a cytokine produced by adipocytes, but paradoxically decreased in obesity, that has been implicated in MM progression. Herein, we evaluated how prolonged exposure to adiponectin affected the survival of MM cells as well as putative signaling mechanisms. Adiponectin activates protein kinase A (PKA), which leads to decreased AKT activity and increased AMP-activated protein kinase (AMPK) activation. AMPK, in turn, induces cell cycle arrest and apoptosis. Adiponectin-induced apoptosis may be mediated, at least in part, by the PKA/AMPK-dependent decline in the expression of the enzyme acetyl-CoA-carboxylase (ACC), which is essential to lipogenesis. Supplementation with palmitic acid, the preliminary end product of fatty acid synthesis, rescues MM cells from adiponectin-induced apoptosis. Furthermore, 5-(tetradecyloxy)-2-furancarboxylic acid (TOFA), an ACC inhibitor, exhibited potent antiproliferative effects on MM cells that could also be inhibited by fatty acid supplementation. Thus, adiponectin's ability to reduce survival of MM cells appears to be mediated through its ability to suppress lipogenesis. Our findings suggest that PKA/AMPK pathway activators, or inhibitors of ACC, may be useful adjuvants to treat MM. Moreover, the antimyeloma effect of adiponectin supports the concept that hypoadiponectinemia as occurs in obesity, promotes MM tumor progression.Leukemia accepted article preview online, 20 March 2014; doi:10.1038/leu.2014.112.Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 03/2014; · 10.16 Impact Factor