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

Kim, Kun Yong; Baek, Ahmi; Hwang, Ji Eun; Choi, Yukyung; Lee, Jeong Eon; Lee, Myeong Sok; Cho, Dea Ho; Lim, Jong‐Seok; Kim, Keun Il; Yang, Young

doi:10.1158/0008-5472.can-08-2641

Cited by 121 publications

(98 citation statements)

References 45 publications

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“…Because of the lack of evidence on AMPK downstream targets, it remains unclear how AMPK activation influences CAR nuclear translocation. Pharmacological activation of AMPK seems to down-regulate HSP70 and EGFR and activate PP2A, suggesting that AMPK may trigger CAR nuclear translocation through the regulation of suppressive proteins [33][34][35] . In addition, how some of the coactivators drive ligand-independent nuclear translocation of CAR in vivo is still unclear.…”

Section: Nuclear Translocation Of Carmentioning

confidence: 99%

Deciphering the roles of the constitutive androstane receptor in energy metabolism

et al. 2014

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The constitutive androstane receptor (CAR) is initially defined as a xenobiotic nuclear receptor that protects the liver from injury. Detoxification of damaging chemicals is achieved by CAR-mediated induction of drug-metabolizing enzymes and transporters. More recent research has implicated CAR in energy metabolism, suggesting a therapeutic potential for CAR in metabolic diseases, such as type 2 diabetes and obesity. A better understanding of the mechanisms by which CAR regulates energy metabolism will allow us to take advantage of its effectiveness while avoiding its side effects. This review summarizes the current progress on the regulation of CAR nuclear translocation, upstream modulators of CAR activity, and the crosstalk between CAR and other transcriptional factors, with the aim of elucidating how CAR regulates glucose and lipid metabolism.

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Section: Nuclear Translocation Of Carmentioning

confidence: 99%

Deciphering the roles of the constitutive androstane receptor in energy metabolism

et al. 2014

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“…1B). Because EL4 tumor growth was inhibited in the absence of APN, it is possible that APN could increase EL4 cell proliferation in vitro (22). To determine whether APN directly affected EL4 cell proliferation, EL4 cells were treated with rAPN.…”

Section: El4 Lymphoma Growth Was Suppressed In Apnko Micementioning

confidence: 99%

Adiponectin Deficiency Suppresses Lymphoma Growth in Mice by Modulating NK Cells, CD8 T Cells, and Myeloid-Derived Suppressor Cells

Han

Jeong

Lee

et al. 2013

The Journal of Immunology

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Previously, we found that adiponectin (APN) suppresses IL-2–induced NK cell activation by downregulating the expression of the IFN-γ–inducible TNF-related apoptosis-inducing ligand and Fas ligand. Although the antitumor function of APN has been reported in several types of solid tumors, with few controversial results, no lymphoma studies have been conducted. In this study, we assessed the role of APN in immune cell function, including NK cells, CTLs, and myeloid-derived suppressor cells, in EL4 and B16F10 tumor-bearing APN knockout (KO) mice. We observed attenuated EL4 growth in the APNKO mice. Increased numbers of splenic NK cells and splenic CTLs were identified under naive conditions and EL4-challenged conditions, respectively. In APNKO mice, splenic NK cells showed enhanced cytotoxicity with and without IL-2 stimulation. Additionally, there were decreased levels of myeloid-derived suppressor cell accumulation in the EL4-bearing APNKO mice. Enforced MHC class I expression on B16F10 cells led to attenuated growth of these tumors in APNKO mice. Thus, our results suggest that EL4 regression in APNKO mice is not only due to an enhanced antitumor immune response but also to a high level of MHC class I expression.

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“…These observations imply that Akt and AMPK have mutual inhibitory effects, and quercetin modulates both of these molecules through up-or downregulating ability in controlling cell growth or apoptosis. Recent reports have shown that suppression of Akt by AMPK is mediated through the activation of phosphatase and tensin homologue (PTEN) or PP2A, and the involvement of IRS-1 between Akt and AMPK was suggested (11,12,20). On the other hand, the inhibitory effect of Akt on AMPK was explained by either alteration of intracellular ATP by Akt or the regulatory activities of Akt on AMPK upstream kinases or phosphatases (13,21 Because of the bidirectional relationship that occurs between Akt and AMPK following quercetin treatment, we hypothesized that quercetin may cause these two proteins to bind to each other.…”

Section: Discussionmentioning

confidence: 99%

“…Observations that AMPK activators are capable of dephosphorylating Akt evoked the importance of the regulation of AMPK/Akt pathway with chemo-preventive agents in cancer control (10)(11)(12). Furthermore, the Akt/TSC2/mTOR signaling pathway via the activation of AMPK has been proposed as a promising approach for tumor suppression.…”

Section: Introductionmentioning

confidence: 99%

“…Several researchers have highlighted the controversial regulation between Akt and AMPK in several cancer cell models. In MDA-MB-231 cells, adiponectin-activated AMPK inhibits Akt through the activation of protein phosphatase 2A (PP2A), which directly dephosphorylates Akt (11). In other cell models of MCF-7 it was shown that the activated AMPK with anti-cancer agent blocked phosphorylation of Akt (12).…”

Section: Introductionmentioning

confidence: 99%

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Regulation of mutual inhibitory activities between AMPK and Akt with quercetin in MCF-7 breast cancer cells

Lee

Park²

2010

Oncol Rep

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Abstract. In lieu of elucidating bidirectional connecting mechanism between AMP-activated protein kinase (AMPK) and survival signal Akt we applied MCF-7 breast cancer cells to determine whether AMPK modulation alters Akt signals and vice versa. Suppression of Akt activities with a synthetic Akt inhibitor alleviated AMPK activities suggesting that Akt is capable of inhibiting AMPK. Also the activation of AMPK with quercetin strongly abrogated Akt activities. Treating cancer cells with AMPK siRNA or Compound C resulted in marked increment of Akt dephosphorylation indicating that AMPK has antagonistic activities towards Akt. However, quercetin exerted Akt inhibitory activities in the absence of AMPK activation. Quercetin induced partial co-localization of phospho-Akt and phospho-AMPK in the nucleus even though their interaction seems to be indirect since the immunoprecipitation data indicate there was no direct binding between total Akt and AMPK. These results suggest there is a mutual suppressive interaction between AMPK and Akt. The investigation of mutual suppression between Akt and AMPK by chemo-preventive agents such as quercetin may provide a mechanistic rational for controlling breast tumor cell growth.

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

Cited by 121 publications

References 45 publications

Deciphering the roles of the constitutive androstane receptor in energy metabolism

Deciphering the roles of the constitutive androstane receptor in energy metabolism

Adiponectin Deficiency Suppresses Lymphoma Growth in Mice by Modulating NK Cells, CD8 T Cells, and Myeloid-Derived Suppressor Cells

Regulation of mutual inhibitory activities between AMPK and Akt with quercetin in MCF-7 breast cancer cells

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