Advanced Glycation End Products Down-regulate Gap Junctions in Human Hepatoma SKHep 1 Cells via the Activation of Src-Dependent ERK1/2 and JNK/SAPK/AP1 Signaling Pathways

Lin, Feng; Chang, Chi I.; Chuang, Kui-Hao; Wang, Chi Y.; Liu, Hung-Jen

doi:10.1021/jf904240c

Cited by 7 publications

(7 citation statements)

References 32 publications

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“…JNK/SAPK inhibitors significantly reversed the decrease in Cx32 and Cx43 protein expression [ 19 ]. To further evaluate the roles of the transcription factors NF-κB and AP-1/c-Jun in the regulation of Cx43, H9C2 cells were cultured in the presence of specific inhibitors of NF-κB or AP-1/c-Jun and total Cx43 protein expression was assessed by Western blot analysis.…”

Section: Resultsmentioning

confidence: 99%

Hypoxia induces connexin 43 dysregulation by modulating matrix metalloproteinases via MAPK signaling

et al. 2013

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Connexin 43 (Cx43) is a major structural protein found in the gap junctions of the ventricular myocardium and a major determinant of its electrical properties. The effects of matrix metalloproteinases (MMPs), the mitogen-activated protein kinase (MAPK) signaling pathway, transcription factor NF-kB, and activator protein-1 (AP-1)/c-Jun on the regulation of Cx43 gene expression in H9c2 cardiomyocytes were assessed. The MAPK signaling pathway (MEK/ERK1/2 and PI3K) and transcription factors NF-kB and AP-1/c-Jun were inhibited, then Cx43 expression was assessed using Western blot analysis, and MMP-9 activity was assessed using gelatin zymography. Hypoxia decreased the Cx43 protein level by approximately 30–50 %. Doxycycline (10 μg/mL), an inhibitor of MMP, markedly attenuated the hypoxia-induced downregulation of Cx43 protein expression at 6 h. The hypoxia-induced decrease in Cx43 protein expression was significantly reversed by U0126 (10 μM), a MEK/ERK1/2 inhibitor, at 6 and 12 h; LY294002 (30 μM), a PI3K inhibitor, downregulated Cx43 expression. Hypoxia-induced MMP-9 activation was inhibited by treatment with LY294002, U0126, and, most especially, U0126. JSH-23 (30 μM), an NF-kB inhibitor, and SP600125 (10 μM), an AP-1/c-Jun inhibitor, attenuated the loss of Cx43. These results suggest that MAPK signaling and the activities NF-kB and MMPs play an important roles in the regulation of Cx43 expression.

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Section: Resultsmentioning

confidence: 99%

Hypoxia induces connexin 43 dysregulation by modulating matrix metalloproteinases via MAPK signaling

et al. 2013

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“…But, it was not consistent with the results of AGE on Cx43 in other cell lines. It has been demonstrated that in human hepatoma cell line (SKHep1) [27] and human aortic endothelial cells (HAEC) [28], the Cx43 protein was reduced by AGE treatment, while Rubenstein et al [29] recently reported that AGE did not alter the Cx43 expression in endothelial cells. The different effect of AGE might be partly associated with the treated cell lines; even the proliferation rate differed in AGE-treated SKHep1 and HAEC.…”

Section: Resultsmentioning

confidence: 99%

Advanced Glycation End Product (AGE)-AGE Receptor (RAGE) System Upregulated Connexin43 Expression in Rat Cardiomyocytes via PKC and Erk MAPK Pathways

Lu¹,

Zhao²,

Xu³

et al. 2013

IJMS

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The remodeling of cardiac gap junction contributes to the arrhythmias in a diabetic heart. We previously reported that high glucose reduced Cx43 protein level in neonatal rat cardiomyocytes. But, the effect and mechanisms of advanced glycation end product (AGE) on Cx43 expression still remain unclear. In this study, we measured the AGE receptor (RAGE) and Cx43 expression by immunohistochemisty in AGE-infused Sprague-Dawley (SD) rats. In vitro, the Cx43 and RAGE levels were detected in AGE-treated cardiomyocytes by Western blot and real-time RT-PCR. The function of cells coupling was measured by Scrap loading dye transfer assay. Our results showed that the AGE-infused rat hearts exhibited increased cardiac RAGE and Cx43, as well as Cx43 redistribution. In cultured cardiomyocytes, AGE elevated RAGE expression in a time- and dose-dependent manner. Cx43 protein and mRNA levels were upregulated by AGE (200 mg/L, 24 h), but the gap junction function was not enhanced. RAGE-targeted knock-down or the addition of PKC, and Erk inhibitors abolished the effect of AGE on Cx43. Therefore, AGE-RAGE system might elevate Cx43 expression in rat cardiomyocytes by activating PKC and Erk MAPK pathways, and it also enhanced Cx43 redistribution in vivo, which might contribute to the arrhythmias in diabetes.

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“…5 ). Earlier studies revealed that Src mediates RalA- and advanced glycation end product-induced AP1 activation [ 46 , 47 ]. COX-2-facilitated cell migration was shown to be associated with Src signaling [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

Suppression of lung cancer progression by isoliquiritigenin through its metabolite 2, 4, 2’, 4’-Tetrahydroxychalcone

Chen

Shenoy

Padia

et al. 2018

J Exp Clin Cancer Res

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BackgroundLicorice is an herb extensively used for both culinary and medicinal purposes. Various constituents of licorice have been shown to exhibit anti-tumorigenic effect in diverse cancer types. However, majority of these studies focus on the aspect of their growth-suppressive role. In this study, we systematically analyzed known licorice’s constituents on the goal of identifying component(s) that can effectively suppress both cell migration and growth.MethodsEffect of licorice’s constituents on cell growth was evaluated by MTT assay while cell migration was assessed by both wound-healing and Transwell assays. Cytoskeleton reorganization and focal adhesion assembly were visualized by immunofluorescence staining with labeled phalloidin and anti-paxillin antibody. Activity of Src in cells was judged by western blot using phosphor-Src416 antibody while Src kinase activity was measured using Promega Src kinase assay system. Anti-tumorigenic capabilities of isoliquiritigenin (ISL) and 2, 4, 2′, 4’-Tetrahydroxychalcone (THC) were investigated using lung cancer xenograft model.ResultsUsing a panel of lung cancer cell lines, ISL was identified as the only licorice’s constituent capable of inhibiting both cell migration and growth. ISL-led inhibition in cell migration resulted from impaired cytoskeleton reorganization and focal adhesion assembly. Assessing the phosphorylation of 141 cytoskeleton dynamics-associated proteins revealed that ISL reduced the abundance of Tyr421-phosphorylation of cortactin, Tyr925- and Tyr861-phosphorylation of FAK, indicating the involvement of Src because these sites are known to be phosphorylated by Src. Enigmatically, ISL inhibited Src in cells while displayed no effect on Src activity in cell-free system. The discrepancy was explained by the observation that THC, one of the major ISL metabolite identified in lung cancer cells abrogated Src activity both in cells and cell-free system. Similar to ISL, THC deterred cell migration and abolished cytoskeleton reorganization/focal adhesion assembly. Furthermore, we showed both ISL and THC suppressed in vitro lung cancer cell invasion and in vivo tumor progression.ConclusionOur study suggests that ISL inhibits lung cancer cell migration and tumorigenesis by interfering with Src through its metabolite THC. As licorice is safely used for culinary purposes, our study suggests that ISL or THC may be safely used as a Src inhibitor.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0902-4) contains supplementary material, which is available to authorized users.

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Advanced Glycation End Products Down-regulate Gap Junctions in Human Hepatoma SKHep 1 Cells via the Activation of Src-Dependent ERK1/2 and JNK/SAPK/AP1 Signaling Pathways

Cited by 7 publications

References 32 publications

Hypoxia induces connexin 43 dysregulation by modulating matrix metalloproteinases via MAPK signaling

Hypoxia induces connexin 43 dysregulation by modulating matrix metalloproteinases via MAPK signaling

Advanced Glycation End Product (AGE)-AGE Receptor (RAGE) System Upregulated Connexin43 Expression in Rat Cardiomyocytes via PKC and Erk MAPK Pathways

Suppression of lung cancer progression by isoliquiritigenin through its metabolite 2, 4, 2’, 4’-Tetrahydroxychalcone

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