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: Obesity is characterized by hyperleptinaemia and hypoadiponectinaemia and these metabolic abnormalities may contribute to the progression of several obesity-associated cancers including oesophageal adenocarcinoma (OAC). We have examined the effects of leptin and adiponectin on OE33 OAC cells. Leptin stimulated proliferation, invasion and migration and inhibited apoptosis in a STAT3-dependant manner. Leptin-stimulated MMP-2 secretion in a partly STAT3-dependent manner and MMP-9 secretion via a STAT3-independent pathway. Adiponectin inhibited leptin-induced proliferation, migration, invasion, MMP secretion and reduced the anti-apoptotic effects: these effects of adiponectin were ameliorated by both a non-specific tyrosine phosphatase inhibitor and a specific PTP1B inhibitor. Adiponectin reduced leptin-stimulated JAK2 activation and STAT3 transcriptional activity in a PTP1B-sensitive manner and adiponectin increased both PTP1B protein and activity. We conclude that adiponectin restrains leptin-induced signalling and pro-carcinogenic behaviour by inhibiting the early events in leptin-induced signal transduction by activating PTP1B. Relative adiponectin deficiency in obesity may contribute to the promotion of OAC.Molecular and Cellular Endocrinology 08/2013; 382(1). DOI:10.1016/j.mce.2013.08.013 · 4.24 Impact Factor
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ABSTRACT: The molecular effects of obesity are mediated by alterations in the levels of adipocytokines. High leptin level associated with obese state is a major cause of breast cancer progression and metastasis, whereas adiponectin is considered a "guardian angel adipocytokine" for its protective role against various obesity-related pathogenesis including breast cancer. In the present study, investigating the role of adiponectin as a potential inhibitor of leptin, we show that adiponectin treatment inhibits leptin-induced clonogenicity and anchorage-independent growth. Leptin-stimulated migration and invasion of breast cancer cells is also effectively inhibited by adiponectin. Analyses of the underlying molecular mechanisms reveal that adiponectin suppresses activation of two canonical signaling molecules of leptin signaling axis: extracellular signal-regulated kinase (ERK) and Akt. Pretreatment of breast cancer cells with adiponectin protects against leptin-induced activation of ERK and Akt. Adiponectin increases expression and activity of the physiological inhibitor of leptin signaling, protein tyrosine phosphatase 1B (PTP1B), which is found to be integral to leptin-antagonist function of adiponectin. Inhibition of PTP1B blocks adiponectin-mediated inhibition of leptin-induced breast cancer growth. Our in vivo studies show that adenovirus-mediated adiponectin treatment substantially reduces leptin-induced mammary tumorigenesis in nude mice. Exploring therapeutic strategies, we demonstrate that treatment of breast cancer cells with rosiglitazone results in increased adiponectin expression and inhibition of migration and invasion. Rosiglitazone treatment also inhibits leptin-induced growth of breast cancer cells. Taken together, these data show that adiponectin treatment can inhibit the oncogenic actions of leptin through blocking its downstream signaling molecules and raising adiponectin levels could be a rational therapeutic strategy for breast carcinoma in obese patients with high leptin levels.Neoplasia (New York, N.Y.) 01/2013; 15(1):23-38. DOI:10.1593/neo.121502 · 5.40 Impact Factor
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ABSTRACT: AMP-activated protein kinase (AMPK) is activated by upstream kinases and negatively regulated by protein phosphatases. Intracellular calcium mediates protein phosphatase 2A (PP2A), which is in a heterotrimeric complex with the PR72 subunit. The PR72 subunit contains two calcium-binding sites formed by EF hands. Our previous study has shown that chronic calcium exposure decreases AMPK activity. To define the specific molecular mechanism whereby calcium can deactivate AMPK, activities of AMPK and PP2A were analyzed in C2C12 muscle cell cultures and skeletal muscle tissues from mutant pigs possessing the AMPKγ3-mutation or the ryanodine receptor (RyR1) calcium gating mutation, or both. C2C12 myotubes treated with calcium releasing agent (caffeine) for 10h decreased (P<0.05) AICAR-induced AMPK activity to control levels and this negative effect was eliminated by ryanodine receptor stabilizer, dantrolene. Interestingly, muscle from pigs with the RyR1 mutation and C2C12 cells administered with 10h caffeine showed higher (P<0.05) PP2A activity compared to controls. More importantly, the inhibitory effect of caffeine on AMPK activity was attenuated by the PP2A inhibitor, calyculin A or siRNA induced knockdown of PP2A. These data show the inhibitory effect of chronic calcium on AMPK activity is exerted through the activation of PP2A.Cell calcium 01/2013; DOI:10.1016/j.ceca.2012.12.001 · 4.21 Impact Factor