title: Protein kinase C isozymes regulate matrix metalloproteinase-1 expression and cell invasion in Helicobacter pylori infection.
abstract: BACKGROUND
  Protein kinase C (PKC) signalling is often dysregulated in gastric cancer and therefore represents a potential target in cancer therapy. The Gram-negative bacterium Helicobacter pylori, which colonises the human stomach, plays a major role in the development of gastritis, peptic ulcer and gastric adenocarcinoma.
  
  
  OBJECTIVE
  To analyse the role of PKC isozymes as mediators of H pylori-induced pathogenesis.
  
  
  METHODS
  PKC phosphorylation was evaluated by immunoblotting and immunohistochemistry. Gene reporter assays, RT-PCR and invasion assays were performed to assess the role of PKC in the regulation of activator protein-1 (AP-1), matrix metalloproteinase-1 (MMP-1) and the invasion of H pylori-infected epithelial cells.
  
  
  RESULTS
  H pylori induced phosphorylation of PKC isozymes α, δ, θ in AGS cells, which was accompanied by the phosphorylation of PKC substrates, including PKCμ and myristoylated alanine-rich C kinase substrate (MARCKS), in a CagA-independent manner. Phospholipase C, phosphatidylinositol 3-kinase and Ca(2+) were crucial for PKC activation on infection; inhibition of PKC diminished AP-1 induction and, subsequently, MMP-1 expression. Invasion assays confirmed PKC involvement in H pylori-induced MMP-1 secretion. In addition, analysis of biopsies from human gastric mucosa showed increased phosphorylation of PKC in active H pylori gastritis and gastric adenocarcinoma.
  
  
  CONCLUSIONS
  The targeting of certain PKC isozymes might represent a suitable strategy to interfere with the MMP-1-dependent remodelling of infected tissue and to overcome the invasive behaviour of gastric cancer cells.
authors.affiliation: Medical Faculty, Institute of Experimental Internal Medicine, Otto von Guericke University, Leipziger Str. 44, 39120 Magdeburg, Germany. olga.sokolova@med.ovgu.de
authors.forename: Olga
authors.initials: O
authors.lastname: Sokolova
authors.forename: Michael
authors.initials: M
authors.lastname: Vieth
authors.forename: Michael
authors.initials: M
authors.lastname: Naumann
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002118:Calcium / Q000378:metabolism; D002465:Cell Movement; D004789:Enzyme Activation; D005753:Gastric Mucosa / Q000201:enzymology; D005756:Gastritis / Q000382:microbiology; D005786:Gene Expression Regulation; D016481:Helicobacter Infections / Q000201:enzymology*; D016480:Helicobacter pylori / Q000472:pathogenicity*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000502:physiology; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D013274:Stomach Neoplasms / Q000201:enzymology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D010738:Type C Phospholipases / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D007527:Isoenzymes; D018808:Transcription Factor AP-1; D058539:Phosphatidylinositol 3-Kinase; D011493:Protein Kinase C; D010738:Type C Phospholipases; D020781:Matrix Metalloproteinase 1; D002118:Calcium