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

Neoplasia. 2016 Apr;18(4):242-52. doi: 10.1016/j.neo.2016.03.001.

Abstract

Helicobacter pylori infection is the strongest risk factor for development of gastric cancer. Host cellular stress responses, including inflammatory and immune responses, have been reported highly linked to H. pylori-induced carcinogenesis. However, whether mitochondrial regulation and metabolic reprogramming, which are potently associated with various cancers, play a role in H. pylori-induced gastric carcinogenesis is largely unknown. Here we revealed that Lon protease (Lonp1), which is a key inductive of mitochondrial unfolded protein response (UPR(mt)) and is required to maintain the mitochondrial quality, was greatly induced in H. pylori infected gastric epithelial cells. Importantly, we uncovered that knockdown of Lonp1 expression significantly diminished the metabolic switch to glycolysis and gastric cell proliferation associated with low multiplicity of H. pylori infection. In addition, Lonp1 overexpression in gastric epithelial cells also promoted glycolytic switch and cell overgrowth, suggesting H. pylori effect is Lonp1 dependent. We further demonstrated that H. pylori induced Lonp1 expression and cell overgrowth, at least partially, via HIF-1α regulation. Collectively, our results concluded the relevance of Lonp1 for cell proliferation and identified Lonp1 as a key regulator of metabolic reprogramming in H. pylori-induced gastric carcinogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Dependent Proteases / genetics
  • ATP-Dependent Proteases / metabolism*
  • Animals
  • Cell Proliferation
  • Cell Transformation, Neoplastic / metabolism*
  • Cells, Cultured
  • Cluster Analysis
  • Epithelial Cells / metabolism
  • Epithelial Cells / microbiology
  • Gastric Mucosa / metabolism
  • Gastric Mucosa / microbiology
  • Gastric Mucosa / pathology
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Glycolysis
  • Helicobacter Infections / complications*
  • Helicobacter Infections / microbiology*
  • Helicobacter pylori*
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Mice
  • Mitochondria / metabolism
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism*
  • Models, Biological
  • Stomach Neoplasms / etiology*
  • Stomach Neoplasms / metabolism*

Substances

  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Mitochondrial Proteins
  • ATP-Dependent Proteases
  • LONP1 protein, human