Role of Glycogen Synthase Kinase-3 in Cell Fate and Epithelial-Mesenchymal Transitions

Doble, Bradley W.; Woodgett, James R.

doi:10.1159/000101306

Cited by 165 publications

(138 citation statements)

References 202 publications

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“…GSK3, which is inhibited noncompetitively by lithium (16,17), has been studied extensively for its role in cell proliferation and epithelial-mesenchymal transition (13). In our study, lithium treatment resulted in a marked increase in phosphorylated (inactive) GSK3␤, in line with previous studies (18).…”

Section: Regulation Of Pkb/akt By Lithium and Its Role In Cell Survivalsupporting

confidence: 91%

Proteomic analysis of lithium-induced nephrogenic diabetes insipidus: Mechanisms for aquaporin 2 down-regulation and cellular proliferation

Nielsen

Hoffert

Knepper

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

110

103

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Lithium is a commonly prescribed mood-stabilizing drug. However, chronic treatment with lithium induces numerous kidney-related side effects, such as dramatically reduced aquaporin 2 (AQP2) abundance, altered renal function, and structural changes. As a model system, inner medullary collecting ducts (IMCD) isolated from rats treated with lithium for either 1 or 2 weeks were subjected to differential 2D gel electrophoresis combined with mass spectrometry and bioinformatics analysis to identify (i) signaling pathways affected by lithium and (ii) unique candidate proteins for AQP2 regulation. After 1 or 2 weeks of lithium treatment, we identified 6 and 74 proteins with altered abundance compared with controls, respectively. We randomly selected 17 proteins with altered abundance caused by lithium treatment for validation by immunoblotting. Bioinformatics analysis of the data indicated that proteins involved in cell death, apoptosis, cell proliferation, and morphology are highly affected by lithium. We demonstrate that members of several signaling pathways are activated by lithium treatment, including the PKB/Akt-kinase and the mitogen-activated protein kinases (MAPK), such as extracellular regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK), and p38. Lithium treatment increased the intracellular accumulation of ␤-catenin in association with increased levels of phosphorylated glycogen synthase kinase type 3␤ (GSK3␤). This study provides a comprehensive analysis of the proteins affected by lithium treatment in the IMCD and, as such, provides clues to potential lithium targets in the brain.L ithium administration is the most popular therapeutic approach to treat bipolar disorders, with 0.1% of the population receiving lithium (1, 2). In 50% of these patients, chronic lithium treatment is associated with altered renal function and nephrogenic diabetes insipidus (NDI) characterized by a defective urinary concentrating mechanism that manifests in polyuria, increased sodium excretion, and hypercholoremic metabolic acidosis (3). The polyuria is largely explained by decreased abundances of the vasopressin (AVP)-regulated aquaporin 2 and aquaporin 3 (AQP2 and AQP3) water channels in the collecting duct (4, 5). The renal sodium loss is likely to be caused by reduced expression of the epithelial sodium channel (ENaC) in the cortical and outer medullary collecting duct (6, 7). In addition, lithium induces increased expression of important acid-base transporting proteins including the H ϩ -ATPase and the anion exchanger type 1 (AE1) in the collecting duct (8). These changes may be, at least in part, attributable to an increase in the proportion of intercalated cells compared with principal cells (9), which is associated with increased cell proliferation and apoptosis of principal cells (10). Additionally, further ''remodeling'' of the kidney can occur with lithium treatment, including major structural changes such as medullary tubular cysts and tubular atrophy, resulting in tubulointerstitial fibrosis and renal failure (11)....

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Section: Regulation Of Pkb/akt By Lithium and Its Role In Cell Survivalsupporting

confidence: 91%

Proteomic analysis of lithium-induced nephrogenic diabetes insipidus: Mechanisms for aquaporin 2 down-regulation and cellular proliferation

Nielsen

Hoffert

Knepper

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

110

103

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“…The loss of E-cadherin is associated with poor clinical outcomes in cancer cells (42,43). Besides participation in tumor growth, GSK-3b is also involved in neoplastic transformation and metastasis (45,46). GSK-3b directly phosphorylate b-catenin and transcriptional repressors of E-cadherin to promote degradation of these proteins.…”

Section: Discussionmentioning

confidence: 99%

TNF-α Induces Epithelial–Mesenchymal Transition of Renal Cell Carcinoma Cells via a GSK3β-Dependent Mechanism

Tang

Chuang

et al. 2012

Molecular Cancer Research

107

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TNF-a is a cytokine with antitumorigenic property. In contrast, low dose, chronic TNF-a production by tumor cells or stromal cells may promote tumor growth and metastasis. Serum levels of TNF-a are significantly elevated in renal cell carcinoma (RCC) patients. Here, we showed that TNF-a induced epithelial-mesenchymal transition (EMT) and promoted tumorigenicity of RCC by repressing E-cadherin, upregulating vimentin, activating MMP9, and invasion activities. In addition, TNF-a treatment inhibited glycogen synthase kinase 3b (GSK-3b) activity through serine-9 phosphorylation mediated by the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway in RCC cells. Inhibition of PI3K/AKT by LY294002 reactivated GSK-3b and suppressed the TNFa-induced EMT of RCC cells. Inactivation of GSK-3b by LiCl significantly increased MMP9 activity and EMT of RCC cells. Activation of GSK-3b by transduction of constitutively active GSK-3b into RCC cells suppressed TNFa-mediated anchorage-independent growth in soft agar and tumorigenicity in nude mice. Overexpression of a kinase-deficient GSK-3b, in contrast, potentiated EMT, anchorage-independent growth and drastically enhanced tumorigenicity in vivo. Most importantly, a 15-fold inactivation of GSK-3b activity, 3-fold decrease of E-cadherin, and 2-fold increase of vimentin were observed in human RCC tumor tissues. These results indicated that inactivation of GSK-3b plays a pivotal role in the TNF-a-mediated tumorigenesis of RCC. Mol Cancer Res; 10(8); 1109-19. Ó2012 AACR. IntroductionRenal cell carcinoma (RCC) is the tenth most common cause of cancer-related deaths worldwide (1). Although surgery is often curative, 30% of patients will present with metastases at the time of initial diagnosis (1). The 5-year survival rate is only 5% in metastatic RCC as advanced RCC is resistant to chemotherapy and radiotherapy (2, 3). Previous studies indicated immunotherapy is relatively effective against RCC (2, 3). However, the response rate is only 15% to 20% (1-3). Therefore, defining the factors involved in disease progression and metastasis will provide novel molecular targets for the development of effective therapies.

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“…Another pathway that received much attention lately with respect to its role in EMT is Wnt signaling (14). In fact, evidence from expression studies in patient tumor specimens, transgenic animals, and in vitro experiments, all confirmed inappropriate activation of the canonical Wnt signaling as a major feature in human neoplasia (15).…”

Section: Introductionmentioning

confidence: 99%

Identification, Mechanism of Action, and Antitumor Activity of a Small Molecule Inhibitor of Hippo, TGF-β, and Wnt Signaling Pathways

Basu

Lettan

Damodaran

et al. 2014

Molecular Cancer Therapeutics

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Embryonic signaling pathways, in particular those mediated by Wnt and TGF-b, are known to play key roles in tumor progression through the induction of epithelial-mesenchymal transition (EMT). Their simultaneous targeting could therefore represent a desirable anticancer strategy. On the basis of recent findings that both Wnt and TGF-b-associated pathways are regulated by Hippo signaling in mammalian cells, we reasoned that targeting the latter would be more effective in inhibiting EMT. In a search for such inhibitors, we identified a small molecule (C19) with remarkable inhibitory activity not only against Hippo, but also against Wnt and TGF-b pathways. C19 inhibited cancer cell migration, proliferation, and resistance to doxorubicin in vitro, and exerted strong antitumor activity in a mouse tumor model. Mechanistically, C19 induced GSK3-b-mediated degradation of the Hippo transducer TAZ, through activation of the Hippo kinases Mst/Lats and the tumor suppressor kinase AMPK upstream of the degradation complex. Overall, this study identified C19 as a multi-EMT pathway inhibitor with a unique mechanism of action. The findings that both AMPK and Mst/Lats mediate the antitumor activity of C19 shed light on a potential cross-talk between metabolic and organ size control pathways in regulating cancer progression. By simultaneously targeting these two pathways, C19 may represent a new type of agents to suppress cancer progression and/or its recurrence.

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Role of Glycogen Synthase Kinase-3 in Cell Fate and Epithelial-Mesenchymal Transitions

Cited by 165 publications

References 202 publications

Proteomic analysis of lithium-induced nephrogenic diabetes insipidus: Mechanisms for aquaporin 2 down-regulation and cellular proliferation

Proteomic analysis of lithium-induced nephrogenic diabetes insipidus: Mechanisms for aquaporin 2 down-regulation and cellular proliferation

TNF-α Induces Epithelial–Mesenchymal Transition of Renal Cell Carcinoma Cells via a GSK3β-Dependent Mechanism

Identification, Mechanism of Action, and Antitumor Activity of a Small Molecule Inhibitor of Hippo, TGF-β, and Wnt Signaling Pathways

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