ATP-Dependent Lon Protease Contributes to Helicobacter pylori-Induced Gastric Carcinogenesis

Luo, Bin; Wang, Minggang; Hou, Nengyi; Hu, Xiao; Ge, Jia; Qin, Xianpeng; Zuo, Xiaofei; Liu, Yang; Luo, Kun; Song, Wei; Wang, Kang; Pang, Ming

doi:10.1016/j.neo.2016.03.001

Cited by 23 publications

(17 citation statements)

References 49 publications

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“…H. pylori -induced HIF-1α expression is associated with increased expression of Mcl-1, VEGF and Lon protease, via a transcriptional mechanism (Bhattacharyya et al, 2010; Kang et al, 2014; Luo et al, 2016). However, in our hands, we found little evidence for enhanced transcription of typical target genes due to HIF-1α (see Figures 4, 5), despite the notable increase in HIF-1α protein levels and reporter activity (Figure 1C).…”

Section: Discussionmentioning

confidence: 99%

Helicobacter pylori Induced Phosphatidylinositol-3-OH Kinase/mTOR Activation Increases Hypoxia Inducible Factor-1α to Promote Loss of Cyclin D1 and G0/G1 Cell Cycle Arrest in Human Gastric Cells

Canales

Valenzuela

Bravo

et al. 2017

Front. Cell. Infect. Microbiol.

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Helicobacter pylori (H. pylori) is a human gastric pathogen that has been linked to the development of several gastric pathologies, such as gastritis, peptic ulcer, and gastric cancer. In the gastric epithelium, the bacterium modifies many signaling pathways, resulting in contradictory responses that favor both proliferation and apoptosis. Consistent with such observations, H. pylori activates routes associated with cell cycle progression and cell cycle arrest. H. pylori infection also induces the hypoxia-induced factor HIF-1α, a transcription factor known to promote expression of genes that permit metabolic adaptation to the hypoxic environment in tumors and angiogenesis. Recently, however, also roles for HIF-1α in the repair of damaged DNA and inhibition of gene expression were described. Here, we investigated signaling pathways induced by H. pylori in gastric cells that favor HIF-1α expression and the consequences thereof in infected cells. Our results revealed that H. pylori promoted PI3K/mTOR-dependent HIF-1α induction, HIF-1α translocation to the nucleus, and activity as a transcription factor as evidenced using a reporter assay. Surprisingly, however, transcription of known HIF-1α effector genes evaluated by qPCR analysis, revealed either no change (LDHA and GAPDH), statistically insignificant increases SLC2A1 (GLUT-1) or greatly enhance transcription (VEGFA), but in an HIF-1α-independent manner, as quantified by PCR analysis in cells with shRNA-mediated silencing of HIF-1α. Instead, HIF-1α knockdown facilitated G1/S progression and increased Cyclin D1 protein half-life, via a post-translational pathway. Taken together, these findings link H. pylori-induced PI3K-mTOR activation to HIF-1α induced G0/G1 cell cycle arrest by a Cyclin D1-dependent mechanism. Thus, HIF-1α is identified here as a mediator between survival and cell cycle arrest signaling activated by H. pylori infection.

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Section: Discussionmentioning

confidence: 99%

Helicobacter pylori Induced Phosphatidylinositol-3-OH Kinase/mTOR Activation Increases Hypoxia Inducible Factor-1α to Promote Loss of Cyclin D1 and G0/G1 Cell Cycle Arrest in Human Gastric Cells

Canales

Valenzuela

Bravo

et al. 2017

Front. Cell. Infect. Microbiol.

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“…In vitro, Hp-infected gastric epithelial cells have exhibited increased glycolysis and increased expression of Lon protease 1 (Lonp1), a protein that activates the mitochondrial unfolded protein response and maintains mitochondrial function. Correspondingly, knockdown of Lonp1 has been shown to reverse alterations in metabolism that are caused by Hp,4 thereby suggesting that aerobic glycolysis and mitochondrial dysfunction correlate with the genesis of GC. Hp-induced GC is also characterized by higher expression levels of the M2 isoform of pyruvate kinase, PKM2, among other factors that are induced in GC and that affect mitochondrial function 5,6.…”

Section: Helicobacter Pylori Promotes the Genesis Of Gc By Inducing Mmentioning

confidence: 99%

<p>Metabolic reprogramming results in abnormal glycolysis in gastric cancer: a review</p>

Liu¹,

Zhang²,

Wang

et al. 2019

OTT

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The Warburg effect in tumor cells involves the uptake of high levels of glucose, enhanced glycolysis, and the metabolism of pyruvate to lactic acid rather than oxidative phos-phorylation to generate energy under aerobic conditions. This effect is closely related to the occurrence, invasion, metastasis, drug resistance, and poor prognosis of gastric cancer (GC). Current research has further demonstrated that the Warburg effect in GC cells is not only mediated by the glycolysis pathway, but also includes roles for mitochondria, noncoding RNAs, and other proteins that do not directly regulate metabolism. As a result, changes in the glycolysis pathway not only lead to abnormal glucose metabolism, but they also affect mitochondrial functions, cellular processes such as apoptosis and cell cycle regulation, and the metabolism of lipids and amino acids. In this review, we discuss metabolic reprogramming in GC based on glycolysis, a possible link between glucose metabolism, lipid metabolism, and amino acid metabolism, and we clarify the role of mitochondria. We also examine recent studies of metabolic inhibitors in GC.

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“…Many studies found that H. pylori can metabolize glucose by both oxidative and fermentative pathways 49 – 53 . H. pylori infected gastric epithelial cells have exhibited increased glycolysis and increased expression of Lon protease 1 (Lonp1), Lonp1 is a key regulator of metabolic reprogramming in H. pylori -induced gastric carcinogenesis 54 , 55 . We also identified two immune-related pathways, including antigen-processing and presentation pathway as well as autoimmune thyroid disease pathway.…”

Section: Discussionmentioning

confidence: 99%

Glycosaminoglycan biosynthesis pathway in host genome is associated with Helicobacter pylori infection

Wang

et al. 2021

Sci Rep

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Helicobacter pylori is a causative pathogen of many gastric and extra-gastric diseases. It has infected about half of the global population. There were no genome-wide association studies (GWAS) for H. pylori infection conducted in Chinese population, who carried different and relatively homogenous strain of H. pylori. In this work, we performed SNP (single nucleotide polymorphism)-based, gene-based and pathway-based genome-wide association analyses to investigate the genetic basis of host susceptibility to H. pylori infection in 480 Chinese individuals. We also profiled the composition and function of the gut microbiota between H. pylori infection cases and controls. We found several genes and pathways associated with H. pylori infection (P < 0.05), replicated one previously reported SNP rs10004195 in TLR1 gene region (P = 0.02). We also found that glycosaminoglycan biosynthesis related pathway was associated with both onset and progression of H. pylori infection. In the gut microbiome association study, we identified 2 species, 3 genera and several pathways had differential abundance between H. pylori infected cases and controls. This paper is the first GWAS for H. pylori infection in Chinese population, and we combined the genetic and microbial data to comprehensively discuss the basis of host susceptibility to H. pylori infection.

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ATP-Dependent Lon Protease Contributes to Helicobacter pylori-Induced Gastric Carcinogenesis

Cited by 23 publications

References 49 publications

Helicobacter pylori Induced Phosphatidylinositol-3-OH Kinase/mTOR Activation Increases Hypoxia Inducible Factor-1α to Promote Loss of Cyclin D1 and G0/G1 Cell Cycle Arrest in Human Gastric Cells

Helicobacter pylori Induced Phosphatidylinositol-3-OH Kinase/mTOR Activation Increases Hypoxia Inducible Factor-1α to Promote Loss of Cyclin D1 and G0/G1 Cell Cycle Arrest in Human Gastric Cells

<p>Metabolic reprogramming results in abnormal glycolysis in gastric cancer: a review</p>

Glycosaminoglycan biosynthesis pathway in host genome is associated with Helicobacter pylori infection

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