Activation of Epidermal Growth Factor Receptor/p38/Hypoxia-inducible Factor-1α Is Pivotal for Angiogenesis and Tumorigenesis of Malignantly Transformed Cells Induced by Hexavalent Chromium

Kim, Donghern; Dai, Jin; Park, Youn-hee; Fai, Leonard Yenwong; Wang, Lei; Pratheeshkumar, Poyil; Son, Young‐Ok; Kondo, Kazuya; Xu, Mei; Luo, Jia; Shi, Xianglin; Zhang, Zhuo

doi:10.1074/jbc.m116.715797

Cited by 38 publications

(26 citation statements)

References 57 publications

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“…The molecular mechanism explaining the differential regulation of HIF-1a accumulation in MoDCs according to TLR stimulation remains to be discovered. In tumor cells, previous studies showed that p38-MAPK could contribute to HIF-1a stabilization (53,54). One possible mechanism proposed by Khurana et al (55) in mouse embryonic fibroblasts is that the RING finger ubiquitin ligase Siah2 can be phosphorylated by p38-MAPK, increasing the degradation of PHD3, therefore reducing HIF-1a degradation.…”

Section: Discussionmentioning

confidence: 98%

Toll-like Receptor 4–Induced Glycolytic Burst in Human Monocyte-Derived Dendritic Cells Results from p38-Dependent Stabilization of HIF-1α and Increased Hexokinase II Expression

Perrin-Cocon

Aublin-Gex

Diaz

et al. 2018

The Journal of Immunology

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Cell metabolism now appears as an essential regulator of immune cells activation. In particular, TLR stimulation triggers metabolic reprogramming of dendritic cells (DCs) with an increased glycolytic flux, whereas inhibition of glycolysis alters their functional activation. The molecular mechanisms involved in the control of glycolysis upon TLR stimulation are poorly understood for human DCs. TLR4 activation of human monocyte-derived DCs (MoDCs) stimulated glycolysis with an increased glucose consumption and lactate production. Global hexokinase (HK) activity, controlling the initial rate-limiting step of glycolysis, was also increased. TLR4-induced glycolytic burst correlated with a differential modulation of HK isoenzymes. LPS strongly enhanced the expression of HK2, whereas HK3 was reduced, HK1 remained unchanged, and HK4 was not expressed. Expression of the other rate-limiting glycolytic enzymes was not significantly increased. Exploring the signaling pathways involved in LPS-induced glycolysis with various specific inhibitors, we observed that only the inhibitors of p38-MAPK (SB203580) and of HIF-1α DNA binding (echinomycin) reduced both the glycolytic activity and production of cytokines triggered by TLR4 stimulation. In addition, LPS-induced HK2 expression required p38-MAPK-dependent HIF-1α accumulation and transcriptional activity. TLR1/2 and TLR2/6 stimulation increased glucose consumption by MoDCs through alternate mechanisms that are independent of p38-MAPK activation. TBK1 contributed to glycolysis regulation when DCs were stimulated via TLR2/6. Therefore, our results indicate that TLR4-dependent upregulation of glycolysis in human MoDCs involves a p38-MAPK-dependent HIF-1α accumulation, leading to an increased HK activity supported by enhanced HK2 expression.

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Section: Discussionmentioning

confidence: 98%

Toll-like Receptor 4–Induced Glycolytic Burst in Human Monocyte-Derived Dendritic Cells Results from p38-Dependent Stabilization of HIF-1α and Increased Hexokinase II Expression

Perrin-Cocon

Aublin-Gex

Diaz

et al. 2018

The Journal of Immunology

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“…Endothelial cells in the coronary arteries form the inner surface of the vessels and drive a response to hypoxic conditions in ischemic heart disease, including coronary atherosclerotic disease or acute coronary syndrome [16]. In response to hypoxic conditions, a number of genes are upregulated by signaling cascades, such as p38 mitogen-activated protein kinase (MAPK), Jun N-terminal kinase (JNK), hypoxia induce factor-1alpha (HIF-1alpha) and ERK, in vascular endothelial cells [17–20]. These responses include vascular-endothelial-cell proliferation, migration, and subsequently angiogenesis, but also growth arrest and apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Tumor Necrosis Factor-Alpha and the ERK Pathway Drive Chemerin Expression in Response to Hypoxia in Cultured Human Coronary Artery Endothelial Cells

Chua

Shyu²,

Lin

et al. 2016

PLoS ONE

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BackgroundChemerin, a novel adipokine, plays a role in the inflammation status of vascular endothelial cells. Hypoxia causes endothelial-cell proliferation, migration, and angiogenesis. This study was aimed at evaluating the protein and mRNA expression of chemerin after exposure of human coronary artery endothelial cells (HCAECs) to hypoxia.Methods and ResultsCultured HCAECs underwent hypoxia for different time points. Chemerin protein levels increased after 4 h of hypoxia at 2.5% O2, with a peak of expression of tumor necrosis factor-alpha (TNF-alpha) at 1 h. Both hypoxia and exogenously added TNF-alpha during normoxia stimulated chemerin expression, whereas an ERK inhibitor (PD98059), ERK small interfering RNA (siRNA), or an anti-TNF-alpha antibody attenuated the chemerin upregulation induced by hypoxia. A gel shift assay indicated that hypoxia induced an increase in DNA-protein binding between the chemerin promoter and transcription factor SP1. A luciferase assay confirmed an increase in transcriptional activity of SP1 on the chemerin promoter during hypoxia. Hypoxia significantly increased the tube formation and migration of HCAECs, whereas PD98059, the anti-TNF-alpha antibody, and chemerin siRNA each attenuated these effects.ConclusionHypoxia activates chemerin expression in cultured HCAECs. Hypoxia-induced chemerin expression is mediated by TNF-alpha and at least in part by the ERK pathway. Chemerin increases early processes of angiogenesis by HCAECs after hypoxic treatment.

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“…Other studies indicated that p38 MAPK inhibits MMP-1 expression (47,48). Although certain studies indicated that p38 MAPK is involved in MMP-1 regulation (45)(46)(47)(48), p38 MAPK did not play a major role in FAM198B-mediated MMP-1 regulation ( Supplementary Fig. S13).…”

Section: Discussionmentioning

confidence: 94%

“…The role of p38 MAPK on MMP-1 expression is controversial in certain situations (45). Recent studies showed that EGFR-mediated p38 MAPK signaling pathway augments MMP-1 expression and then leads to promote cancer tumorigenesis and angiogenesis (46). Other studies indicated that p38 MAPK inhibits MMP-1 expression (47,48).…”

Section: Discussionmentioning

confidence: 99%

FAM198B Is Associated with Prolonged Survival and Inhibits Metastasis in Lung Adenocarcinoma via Blockage of ERK-Mediated MMP-1 Expression

Hsu

Chang

Chen

et al. 2018

Clinical Cancer Research

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The comprehensive understanding of mechanisms involved in the tumor metastasis is urgently needed for discovering novel metastasis-related genes for developing effective diagnoses and treatments for lung cancer. FAM198B was identified from an isogenic lung cancer metastasis cell model by microarray analysis. To investigate the clinical relevance of FAM198B, the FAM198B expression of 95 Taiwan lung adenocarcinoma patients was analyzed by quantitative real-time PCR and correlated to patients' survivals. The impact of FAM198B on cell invasion, metastasis, and tumor growth was examined by cellular assays and mouse models. In addition, the N-glycosylation-defective FAM198B mutants generated by site-directed mutagenesis were used to study protein stability and subcellular localization of FAM198B. Finally, the microarray and pathway analyses were used to elucidate the underlying mechanisms of FAM198B-mediated tumor suppression. We found that the high expression of FAM198B was associated with favorable survival in Taiwan lung adenocarcinoma patients and in a lung cancer public database. Enforced expression of FAM198B inhibited cell invasion, migration, mobility, proliferation, and anchorage-independent growth, and FAM198B silencing exhibited opposite activities FAM198B also attenuated tumor growth and metastasis We further identified MMP-1 as a critical downstream target of FAM198B. The FAM198B-mediated MMP-1 downregulation was via inhibition of the phosphorylation of ERK. Interestingly deglycosylation nearly eliminated the metastasis suppression activity of FAM198B due to a decrease of protein stability. Our results implicate FAM198B as a potential tumor suppressor and to be a prognostic marker in lung adenocarcinoma. .

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Activation of Epidermal Growth Factor Receptor/p38/Hypoxia-inducible Factor-1α Is Pivotal for Angiogenesis and Tumorigenesis of Malignantly Transformed Cells Induced by Hexavalent Chromium

Cited by 38 publications

References 57 publications

Toll-like Receptor 4–Induced Glycolytic Burst in Human Monocyte-Derived Dendritic Cells Results from p38-Dependent Stabilization of HIF-1α and Increased Hexokinase II Expression

Toll-like Receptor 4–Induced Glycolytic Burst in Human Monocyte-Derived Dendritic Cells Results from p38-Dependent Stabilization of HIF-1α and Increased Hexokinase II Expression

Tumor Necrosis Factor-Alpha and the ERK Pathway Drive Chemerin Expression in Response to Hypoxia in Cultured Human Coronary Artery Endothelial Cells

FAM198B Is Associated with Prolonged Survival and Inhibits Metastasis in Lung Adenocarcinoma via Blockage of ERK-Mediated MMP-1 Expression

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