Acidic environment leads to ROS-induced MAPK signaling in cancer cells

PLoS One. 2011;6(7):e22445. doi: 10.1371/journal.pone.0022445. Epub 2011 Jul 26.


Tumor micromilieu often shows pronounced acidosis forcing cells to adapt their phenotype towards enhanced tumorigenesis induced by altered cellular signalling and transcriptional regulation. In the presents study mechanisms and potential consequences of the crosstalk between extra- and intracellular pH (pH(e), pH(i)) and mitogen-activated-protein-kinases (ERK1/2, p38) was analyzed. Data were obtained mainly in AT1 R-3327 prostate carcinoma cells, but the principle importance was confirmed in 5 other cell types. Extracellular acidosis leads to a rapid and sustained decrease of pH(i) in parallel to p38 phosphorylation in all cell types and to ERK1/2 phosphorylation in 3 of 6 cell types. Furthermore, p38 phosphorylation was elicited by sole intracellular lactacidosis at normal pH(e). Inhibition of ERK1/2 phosphorylation during acidosis led to necrotic cell death. No evidence for the involvement of the kinases c-SRC, PKC, PKA, PI3K or EGFR nor changes in cell volume in acidosis-induced MAPK activation was obtained. However, our data reveal that acidosis enhances the formation of reactive oxygen species (ROS), probably originating from mitochondria, which subsequently trigger MAPK phosphorylation. Scavenging of ROS prevented acidosis-induced MAPK phosphorylation whereas addition of H(2)O(2) enhanced it. Finally, acidosis increased phosphorylation of the transcription factor CREB via p38, leading to increased transcriptional activity of a CRE-reporter even 24 h after switching the cells back to a normal environmental milieu. Thus, an acidic tumor microenvironment can induce a longer lasting p38-CREB-medited change in the transcriptional program, which may maintain the altered phenotype even when the cells leave the tumor environment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acids / metabolism*
  • Animals
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Dogs
  • Enzyme Activation / drug effects
  • Extracellular Space / drug effects
  • Extracellular Space / metabolism
  • Humans
  • Hydrogen-Ion Concentration / drug effects
  • Intracellular Space / drug effects
  • Intracellular Space / metabolism
  • MAP Kinase Signaling System* / drug effects
  • Mitogen-Activated Protein Kinases / metabolism*
  • Models, Biological
  • Neoplasms / enzymology*
  • Neoplasms / pathology*
  • Phosphorylation / drug effects
  • Protein Kinase Inhibitors / pharmacology
  • Protein-Tyrosine Kinases / metabolism
  • Rats
  • Reactive Oxygen Species / metabolism*
  • Sodium-Potassium-Exchanging ATPase / metabolism
  • Tumor Microenvironment* / drug effects


  • Acids
  • CREB1 protein, human
  • Cyclic AMP Response Element-Binding Protein
  • Protein Kinase Inhibitors
  • Reactive Oxygen Species
  • Protein-Tyrosine Kinases
  • Mitogen-Activated Protein Kinases
  • Sodium-Potassium-Exchanging ATPase