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

• Published in: PloS one 2011-07, Vol.6 (7), p.e22445-e22445
• Main Authors: Riemann, Anne, Schneider, Bettina, Ihling, Angelika, Nowak, Martin, Sauvant, Christoph, Thews, Oliver, Gekle, Michael
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Acidosis; Acids; Acids - metabolism; Animals; Apoptosis; Autophagy; Biochemistry; Biology; Cancer; Cancer therapies; Cardiomyocytes; Cell death; Cell Line, Tumor; Cell size; Cell Survival - drug effects; Crosstalk; Cyclic AMP response element-binding protein; Cyclic AMP Response Element-Binding Protein - metabolism; Data processing; Dogs; Endoplasmic reticulum; Enzyme Activation - drug effects; Epidermal growth factor receptors; Extracellular signal-regulated kinase; Extracellular Space - drug effects; Extracellular Space - metabolism; Fibroblasts; Gene regulation; Homeostasis; Humans; Hydrogen peroxide; Hydrogen-Ion Concentration - drug effects; Hypoxia; Intracellular; Intracellular Space - drug effects; Intracellular Space - metabolism; Kinases; MAP kinase; MAP Kinase Signaling System - drug effects; Medicine; Metabolism; Mitochondria; Mitogen-Activated Protein Kinases - metabolism; Mitogens; Models, Biological; Neoplasms - enzymology; Neoplasms - pathology; Oxidative stress; Oxygen; pH effects; Phosphorylation; Phosphorylation - drug effects; Phosphotransferases; Physiology; Prostate; Prostate cancer; Prostate carcinoma; Protein kinase A; Protein kinase C; Protein Kinase Inhibitors - pharmacology; Protein-Tyrosine Kinases - metabolism; Rats; Reactive oxygen species; Reactive Oxygen Species - metabolism; Regulation; Rodents; Signaling; Sodium-Potassium-Exchanging ATPase - metabolism; Src protein; Tumor Microenvironment - drug effects; Tumorigenesis; Tumors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0022445

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.