Adiponectin-Activated AMPK Stimulates Dephosphorylation of AKT through Protein Phosphatase 2A Activation
Adiponectin-Activated AMPK Stimulates Dephosphorylation of AKT through Protein Phosphatase 2A Activation
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DOI：
10.1158/0008-5472.can-08-2641
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发表时间：
2009-05-01
期刊：
影响因子：
11.2
通讯作者：
Yang, Young
中科院分区：
文献类型：
--
作者：
Kim, Kun-yong;Baek, Ahmi;Yang, Young
血清脂联素水平低是多种癌症的高危因素。尽管脂联素抑制乳腺癌细胞的增殖和转移，但其潜在的分子机制仍不清楚。在这项研究中，我们发现脂联素激活的 AMPK 通过增加蛋白磷酸酶 2A (PP2A) 活性来刺激 AKT 去磷酸化，从而降低 MDA-MB-231 细胞的侵袭性。在各种调节性 B56 亚基中，B56 γ 直接被 AMPK 在 Ser(298) 和 Ser(336) 处磷酸化，通过 Tyr(307) 处的 PP2Ac 去磷酸化导致 PP2A 活性增加。我们还表明，乳腺癌患者的血液脂联素水平和 PP2A 活性的组织水平均降低，并且将脂联素直接施用到肿瘤组织中会刺激 PP2A 活性。总而言之，这些发现表明，源自脂肪细胞的脂联素通过激活肿瘤抑制因子 PP2A 来负向调节乳腺癌细胞的侵袭性。 [癌症研究 2009;69(9):4018-26]
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 gamma 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. [Cancer Res 2009;69(9):4018-26]