Leptin induces migration and invasion of glioma cells through MMP‐13 production

Yeh, Wei-Lan; Lu, Dah‐Yuu; Lee, Ming-Jen; Fu, Wen‐Mei

doi:10.1002/glia.20773

Cited by 88 publications

(69 citation statements)

References 47 publications

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“…Furthermore, we demonstrated for the first time that leptin activates migration in human GBM cells, which is consistent with the observation that the hormone induces migration of rat C6 glioma cells (22).…”

Section: Discussionsupporting

confidence: 91%

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Metformin inhibits leptin-induced growth and migration of glioblastoma cells

2012

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Abstract. Metformin, a derivative of biguanide, is a first-line therapy for type 2 diabetes mellitus. Since the drug has been shown to significantly reduce the risk of various cancers and cancer mortality in diabetic patients, it is being considered as a potential anticancer therapeutic or preventive agent. In cellular models, metformin inhibits the growth of many types of cancer cells; however, its effects on glioblastoma multiforme (GBM) are not well characterized. Here, we analyzed the effects of metformin on the growth and migration of LN18 and LN229 GBM cells cultured under basal conditions or exposed to leptin, a cytokine that has recently been implicated in GBM development. We found that 2-16 mM metformin reduced basal and leptin-stimulated growth of GBM cells in a dose-dependent manner. Furthermore, the drug significantly inhibited the migration of GBM cells. The action of metformin was mediated through the upregulation of its main signaling molecule, the adenosine monophosphate-activated protein kinase (AMPK), as well as through the downregulation of the signal transducer and activator of transcription 3 (STAT3) and the Akt/PKB serine/threonine protein kinase. In leptin-treated cells, the drug reversed the effects of the cytokine on the AMPK and STAT3 pathways, but modulated Akt activity in a cell-dependent manner. Our results suggest that metformin or similar AMPK-targeting agents with optimized bloodbrain-barrier penetrability could be developed as potential treatments of GBM and could be used in conjunction with other target drugs such as leptin receptor antagonists.

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Section: Discussionsupporting

confidence: 91%

“…Leptin is a recognized motogenic and angiogenic factor in cancer models (21) and induces migration in rat glioma cells (22); however, its role in human GBM migration has never been studied. We found that in LN229 and LN18 cells, leptin increased cell migration by ~50% (Fig.…”

Section: Resultsmentioning

confidence: 99%

Metformin inhibits leptin-induced growth and migration of glioblastoma cells

2012

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“…MMPs are a family of zinc-dependent endopeptidases with 24 identified members (42). There are reports showing that C6 cells express MMP-2, -9, -13, and membrane-type1 MMP (43,44). GM6001 inhibits MMP-1, -2, -3, -8, and -9 (45).…”

Section: Discussionmentioning

confidence: 99%

Tricyclic Antidepressant Amitriptyline Activates Fibroblast Growth Factor Receptor Signaling in Glial Cells

Hisaoka

Tsuchioka

Yano

et al. 2011

Journal of Biological Chemistry

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Brain imaging studies have revealed that both the hippocampus and prefrontal cortex undergo selective volume reduction in major depressive disorder (MDD).2 One of the most consistent findings, associated with the volume reduction, in postmortem studies of MDD is a decrease in the density and number of glia in several cortical areas (1). The decreases in glial density are accompanied by a reduction of astrocytic markers, such as glial fibrillary acidic protein and glutamine synthetase (1, 2), thus suggesting that glia, especially astrocytes might be involved in the pathophysiology of MDD.One of the major role of astrocytes is the production of neurotrophic factors, such as nerve growth factor (NGF), brainderived neurotrophic factor, fibroblast growth factor (FGF), and glial cell line-derived neurotrophic factor (GDNF), which support neurogenesis, gliogenesis, development, plasticity, and survival (3).GDNF, a member of the transforming growth factor-␤ superfamily, was originally purified from a rat glial cell line supernatant as a trophic factor for midbrain dopamine neurons and was later found to have pronounced effects on other neuronal populations and glia (4). GDNF improves cognitive function (5, 6) while also inhibiting drug-induced dependence (7). These results suggest that GDNF plays a crucial role in not only neuronal development but also neuronal and glial plasticity in higher-ordered brain function.A growing body of evidence suggests that GDNF as well as brain-derived neurotrophic factor is involved in the pathophysiology of . GDNF has been shown to decrease in the peripheral blood of patients with MDD (8). In addition, the decreased blood level of GDNF in MDD has been reported to increase after antidepressant treatment (13). We have also previously shown that antidepressants increase the GDNF production in C6 glioma cells (C6 cells), rat astrocytes, and normal human astrocytes (NHA) (14,15). Treatment with antidepressants alters the GDNF levels in rodents in vivo and glial cell culture in vitro (16 -18). These findings suggest that an increase of GDNF production may be involved in the therapeutic effect *

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“…A previous study has shown that C6 cells are a good tool for examining the underlying molecular machinery of clock gene expression because several clock genes are expressed and show the circadian oscillation after exposure to dexamethasone in these cells (20). In addition, we and another laboratory have examined various functions of astrocytes by using C6 cells (19,27). Therefore, although further investigation using by a primary culture of SCN astrocytes is necessary, it is possible that the characteristics of C6 cells might reflect in the SCN astrocytes.…”

Section: Discussionmentioning

confidence: 99%

Noradrenaline Induces Clock Gene Per1 mRNA Expression in C6 Glioma Cells Through β2-Adrenergic Receptor Coupled With Protein Kinase A – cAMP Response Element Binding Protein (PKA–CREB) and Src-Tyrosine Kinase – Glycogen Synthase Kinase-3β (Src–GSK-3β)

et al. 2010

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. Astrocytes in the hypothalamic suprachiasmatic nucleus, site of the master circadian pacemaker, play an essential role in the regulation of systemic circadian rhythms. To evaluate involvement of noradrenergic systems in regulation of circadian variation of clock-genes in astrocytes, we investigated effects of noradrenaline (NA) on expression of several clock genes in C6 glioma cells by using real-time PCR analysis. Treatment with NA (10 μ M) induced transient expression of Per1 mRNA, but not of Per2 , Bmal1 , Clock , Cry1 , or Cry2 mRNA, through activation of β 2 adrenoceptors. Action of NA was partially blocked by H-89 [protein kinase A (PKA) inhibitor] or KG-501 [inhibitor of cAMP response element binding protein (CREB)]. We found that pretreatment with genistein or PP2 (general or Src tyrosine kinase inhibitors, respectively) or LiCl [inhibitor of glycogen synthase kinase-3 β (GSK-3 β )] significantly inhibited NA-induced Per1 mRNA expression. In addition, treatment with H-89 and either genistein or LiCl completely blocked NA stimulatory effects. NA markedly induced tyrosine phosphorylation of Src and GSK-3 β via activation of β 2 adrenoceptors. Phosphorylation of GSK-3 β by NA was completely eliminated by genistein or PP2. These results primarily suggest that two distinct NA-mediating pathways, PKA-CREB and Src-GSK-3 β , play crucial roles in regulation of Per1 expression in astroglial cells.

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Leptin induces migration and invasion of glioma cells through MMP‐13 production

Cited by 88 publications

References 47 publications

Metformin inhibits leptin-induced growth and migration of glioblastoma cells

Metformin inhibits leptin-induced growth and migration of glioblastoma cells

Tricyclic Antidepressant Amitriptyline Activates Fibroblast Growth Factor Receptor Signaling in Glial Cells

Noradrenaline Induces Clock Gene Per1 mRNA Expression in C6 Glioma Cells Through β2-Adrenergic Receptor Coupled With Protein Kinase A – cAMP Response Element Binding Protein (PKA–CREB) and Src-Tyrosine Kinase – Glycogen Synthase Kinase-3β (Src–GSK-3β)

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