Adiponectin-Activated AMPK Stimulates Dephosphorylation of AKT through Protein Phosphatase 2A Activation

Department of Life Science, Research Center for Women's Diseases, Sookmyung Women's University, Seoul, Korea.
Cancer Research (Impact Factor: 9.33). 05/2009; 69(9):4018-26. DOI: 10.1158/0008-5472.CAN-08-2641
Source: PubMed


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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    • "Adiponectin functions as an insulin sensitizer, and low serum adiponectin reversely correlates with insulin resistance [10]. Moreover, adiponectin can inhibit cell proliferation, invasiveness and angiogenesis in vitro by suppression of estrogen receptor α and vascular endothelium growth factor [30-32]. Serum adiponectin would be a protective factor for endometrial cancer. "
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    • "Several previous studies have shown anti-cancer effects of adiponectin in different cell models. Various mechanisms have been reported including inhibition of Akt signalling (Ogunwobi and Beales, 2008a), activation of protein phosphatase 2A (Kim et al., 2009a), activation of 5' AMP-activated kinase (Kim et al., 2009a; Ogunwobi and Beales, 2008a), inhibition of lipogenesis (Kim et al., 2010), regulation of p53 (Dos Santos et al., 2008), induction of Bax and cyclin-dependant kinase inhibitors (Kim et al., 2010) as well as increased SOCS3 expression and enhanced SOCS3 binding to the leptin receptor (Sharma et al., 2010) and because different cell lines, from different tissues with different cell behaviours (proliferation, apoptosis, invasion) have been studied, it is not yet possible to be sure if these represent a co-ordinated signalling "
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    • "There is now firm evidence that PP2A-B55 plays a crucial role in dephosphorylating CDK1 substrates during the mitotic stages and that PP2A-B56 dephosphorylates PLK1 substrates. In addition to the B55 and B56 regulatory subunits of PP2A, many phosphorylation events caused by various PP2A regulatory subunits during cell cycle progression have been elucidated (50-52). In the near future, the reason for some noted phosphorylations on various PP2A regulatory subunits may be understood in terms of cell cycle regulation. "
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