AMP-activated protein kinase inhibits TGF-β-, angiotensin II-, aldosterone-, high glucose-, and albumin-induced epithelial-mesenchymal transition

Lee, Jang Han; Kim, Ji Hyun; Kim, Ja Seon; Chang, Jai Won; Kim, Soon Bae; Park, Jung Sik; Lee, Sang Koo

doi:10.1152/ajprenal.00148.2012

Cited by 106 publications

(94 citation statements)

References 42 publications

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“…A high-glucose-dependent increase of ROS in tubular cells has been described as being caused by the overexpression of Nox4, the isoform of NADPH oxidase responsible for ROS production in several kidney diseases (Lee and Han, 2010;Lee et al, 2013). ROS promoted Arg degradation by ubiquitylation, whereas c-Abl seems to be less sensitive to highglucose-induced ROS (Fig.…”

Section: Discussionmentioning

confidence: 96%

“…It has been described that the MCF-7 and 293 cell line exposure to reactive oxygen species (ROS) induced an increase of Arg ubiquitylation and degradation (Cao et al, 2005), and that highglucose conditions induced ROS overload in tubular cells (Lee et al, 2013). To evaluate whether these molecular mechanisms were even active in our in vitro model, we assayed ROS production in tubular cells and found that high-glucose treatment for 96 h induced a significant increment of ROS level that further increased at 7 days (Fig.…”

Section: High Glucose Induced An Increase In Ubiquitin-dependent Arg mentioning

confidence: 99%

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Arg tyrosine kinase modulates TGF-β1 production in human renal tubular cells under high-glucose conditions

Torsello

Bianchi

Meregalli

et al. 2016

Journal of Cell Science

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Renal tubular cells are involved in the tubular interstitial fibrosis observed in diabetic nephropathy. It is debated whether epithelialmesenchymal transition (EMT) affects tubular cells, which under highglucose conditions overproduce transforming growth factor-β (TGF-β), a fibrogenic cytokine involved in interstitial fibrosis development. Our study investigated the involvement of non-receptor tyrosine kinase Arg (also called Abl2) in TGF-β production. Human primary tubular cell cultures exposed to high-glucose conditions were used. These cells showed an elongated morphology, stress fibers and vimentin increment but maintained most of the epithelial marker expression and distribution. In these cells exposed to high glucose, which overexpressed and secreted active TGF-β1, Arg protein and activity was downregulated. A further TGF-β1 increase was induced by Arg silencing with siRNA, as with the Arg tyrosine kinase inhibitor Imatinib. In the cells exposed to high glucose, reactive oxygen species (ROS)-dependent Arg kinase downregulation induced both RhoA activation, through p190RhoGAPA (also known as ARHGAP35) modulation, and proteasome activity inhibition. These data evidence a new specific involvement of Arg kinase into the regulation of TGF-β1 expression in tubular cells under high-glucose conditions and provide cues for new translational approaches in diabetic nephropathy.

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Section: Discussionmentioning

confidence: 96%

Section: High Glucose Induced An Increase In Ubiquitin-dependent Arg mentioning

confidence: 99%

Arg tyrosine kinase modulates TGF-β1 production in human renal tubular cells under high-glucose conditions

Torsello

Bianchi

Meregalli

et al. 2016

Journal of Cell Science

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“…AMPK has been recently documented to be involved in EMT (Cufi et al, 2010;Vazquez-Martin et al, 2010;Wang et al, 2010Wang et al, , 2014Lee et al, 2013;Chou et al, 2014;Zhang et al, 2014). Its effect was first described in tissue fibrosis, where opposite effects were reported (Wang et al, 2010;Lee et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

AMPK Inhibits the Stimulatory Effects of TGF-βon Smad2/3 Activity, Cell Migration, and Epithelial-to-Mesenchymal Transition

Lin¹,

Li²,

He³

et al. 2015

Mol Pharmacol

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AMP-activated protein kinase (AMPK), an important downstream effector of the tumor suppressor liver kinase 1 (LKB1) and pharmacologic target of metformin, is well known to exert a preventive and inhibitory effect on tumorigenesis; however, its role in cancer progression and metastasis has not been well characterized. The present study investigates the potential roles of AMPK in inhibiting cancer-cell migration and epithelialto-mesenchymal transition (EMT) by regulating the canonical transforming growth factor b (TGF-b) signaling pathway, an important promoting factor for cancer progression. Our results showed that activation of AMPK by metformin inhibited TGF-binduced Smad2/3 phosphorylation in cancer cells in a dosedependent manner. The effect of metformin is dependent on the presence of LKB1. A similar effect was obtained by expressing a constitutive active mutant of AMPKa1 subunit, whereas the expression of a dominant negative mutant of AMPKa1 or ablation of AMPKa subunits greatly enhanced TGF-b stimulation of Smad2/3 phosphorylation. As a consequence, expression of genes downstream of Smad2/3, including plasminogen activator inhibitor-1, fibronectin, and connective tissue growth factor, was suppressed by metformin in a LKB1-dependent fashion. In addition, metformin blocked TGF-b-induced inteleukin-6 expression through both LKB1-dependent and -independent mechanisms. Our results also indicate that activation of LKB1/AMPK inhibits TGF-b-stimulated cancer cell migration. Finally, TGF-b induction of EMT was inhibited by phenformin and enhanced by knockdown of LKB1 expression with shRNA. Together, our data suggest that AMPK could be a drug target for controlling cancer progression and metastasis.

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“…Emerging evidence indicates that LKB1/AMPK inhibits tumor invasion and migration through downregulation of the downstream factors of TGF-β signaling, such as MMPs and Snail (67,68). It was reported that AMPK inhibited TGF-β-induced EMT in HK-2 cells (69). In addition, AICAR, metformin and adiponectin were found to activate AMPK, but inhibited TGF-β-induced fibrosis via downregulation of collagen type I α 1 (COL1A) and α-SMA expression in hepatic stellate cells (70).…”

Section: The Lkb1/ampk Pathway Regulates Cancer Cell Invasion and Migmentioning

confidence: 99%

Role of the LKB1/AMPK pathway in tumor invasion and metastasis of cancer cells (Review)

Huang

Lü

et al. 2015

Oncology Reports

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Abstract. Liver kinase B1 (LKB1), also known as serine/threo nine kinase 11 (STK11), is a tumor suppressor that is inactivated in Peutz-Jeghers familial cancer syndrome. LKB1 phosphorylates and activates AMP-activated protein kinase (AMPK), which negatively regulates cancer cell proliferation and metabolism. However, recent evidence demonstrates that the LKB1/AMPK pathway is involved in the process of tumor invasion and migration, which is an important hallmark of carcinoma progression to higher pathological grades of malignancy. This review focuses on the function of the LKB1/AMPK pathway in the invasion and migration of cancer cells and provides an overview of therapeutic strategies aimed at this pathway in malignant tumors.

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AMP-activated protein kinase inhibits TGF-β-, angiotensin II-, aldosterone-, high glucose-, and albumin-induced epithelial-mesenchymal transition

Cited by 106 publications

References 42 publications

Arg tyrosine kinase modulates TGF-β1 production in human renal tubular cells under high-glucose conditions

Arg tyrosine kinase modulates TGF-β1 production in human renal tubular cells under high-glucose conditions

AMPK Inhibits the Stimulatory Effects of TGF-βon Smad2/3 Activity, Cell Migration, and Epithelial-to-Mesenchymal Transition

Role of the LKB1/AMPK pathway in tumor invasion and metastasis of cancer cells (Review)

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