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

Abstract

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.

Helicobacter pylori Infection Modulates Host Cell Metabolism through VacA-Dependent Inhibition of mTORC1

“…Hp -mediated activation of hemeoxygenase-1 (HO-1), an inflammatory regulator of adaptive immune responses, requires mTORC1 positive regulation (Ko et al, 2016). mTORC1 signaling also mediates hypoxia inducible factor-1α (HIF-1α) driven G 0 /G 1 cell cycle arrest during Hp infection (Canales et al, 2017). Most recently, Hp strains lacking active VacA were demonstrated to negatively regulate autophagy through c-Met-PI3K/Akt-mTOR, by a mechanism involving the Hp type IV secretion effector, cytotoxin-associated gene A (CagA) (Li et al, 2017).…”

Helicobacter pylori promote inflammation and host defense through the cagA‐dependent activation of mTORC1

“…It is reported that activation of phosphatidylinositol‐3‐kinase (PI3K)/AKT could induce mTOR phosphorylation and subsequently induce S6K phosphorylation (Canales et al, 2017). To see whether PI3K/AKT/mTOR/S6K pathway activated in gastric epithelial cells upon H. pylori infection, we blocked PI3K/AKT or mTOR pathway, and then stimulated AGS cells with H. pylori .…”

“…However, the past reports about the mTORC1 pathway in H. pylori infection are rare, especially in cagA ‐dependent manner. H. pylori outer membrane vesicles (OMVs) induce upregulation of Heme oxygenase‐1 requires mTORC1 positive regulation in dendritic cells (Ko et al, 2016), while G0/G1 cell cycle arrest caused by H. pylori in human gastric cells is also through mTORC1 activation (Canales et al, 2017). Interestingly, H. pylori virulence factor VacA seems to have the opposite effect to the OMVs and cagA on mTORC1 and autophagy (I. J. Kim et al, 2018; Ko et al, 2016; Li et al, 2017), which demonstrates there exist a complex signaling network around mTORC1 in the gastric epithelial cells during H. pylori infection.…”

Oral rinses in growth inhibition and treatment of Helicobacter pylori infection

“…Gene profiling of specific gastric cancer marker and H. pylori after oral rinse treatment PTEN, and MMP7 were also included [27][28][29][30]. A mixed expression profile was observed on treatment with oral rinses (B, C, D, and E) for 5 s in the I10 strain.…”