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

¹ Research Center for Women's Diseases, Department of Life Science, Sookmyung Women's University; and ² Department of Surgery, College of Medicine, Yonsei University, Seoul, Korea

Requests for reprints: Young Yang, Research Center for Women's Diseases, Department of Life Science, Sookmyung Women's University, Seoul 140-742, Korea. Phone: 82-2-710-9590; Fax: 82-2-2077-7322; E-mail: yyang{at}sookmyung.ac.kr.

Key Words: adiponectin • metastasis • AKT • AMPK • PP2A

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, B56 was directly phosphorylated by AMPK at Ser²⁹⁸ and Ser³³⁶, leading to an increase of PP2A activity through dephosphorylation of PP2Ac at Tyr³⁰⁷. 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. [Cancer Res 2009;69(9):4018–26]