title: Impact of extracellular acidosis on intracellular pH control and cell signaling in tumor cells.
abstract: Cells in solid tumors generate an extracellular acidosis due to the Warburg effect and tissue hypoxia. Acidosis can affect the functional behavior of tumor cells, causing, e.g., multidrug resistance. In this process ERK1/2 and p38 mitogen-activated protein kinases (MAPK) seem to play a key role. However, the underlying mechanism of MAPK activation by extracellular acidosis remains unclear. Experiments were performed in three tumor and three normal tissue cell lines in which the cells were exposed to an extracellular pH of 6.6 for 3 h. Intracellular pH (pHi), protein expression and activation, acidosis-induced transactivation, and reactive oxygen species (ROS) formation were measured. Extracellular acidosis resulted in a rapid and sustained decrease of pHi leading to a reversal of the extra-/intracellular pH gradient. Extracellular acidosis led to p38 phosphorylation in all cell types and to ERK1/2 phosphorylation in three of six cell lines. Furthermore, p38 phosphorylation was also observed during sole intracellular lactacidosis at normal pHe. Acidosis-enhanced formation of ROS, probably originating from mitochondria, seems to trigger MAPK phosphorylation. Finally, acidosis increased phosphorylation of the transcription factor CREB and resulted in increased transcriptional activity. Thus, an acidic tumor microenvironment can induce a longer-lasting p38 CREB-mediated change in the transcriptional program.
authors.affiliation: Julius-Bernstein Institute of Physiology, Martin-Luther-University of Halle-Wittenberg, Magdeburger Str. 6, 06112, Halle (Saale), Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Riemann
authors.affiliation: Julius-Bernstein Institute of Physiology, Martin-Luther-University of Halle-Wittenberg, Magdeburger Str. 6, 06112, Halle (Saale), Germany.
authors.forename: Angelika
authors.initials: A
authors.lastname: Ihling
authors.affiliation: Julius-Bernstein Institute of Physiology, Martin-Luther-University of Halle-Wittenberg, Magdeburger Str. 6, 06112, Halle (Saale), Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Schneider
authors.affiliation: Julius-Bernstein Institute of Physiology, Martin-Luther-University of Halle-Wittenberg, Magdeburger Str. 6, 06112, Halle (Saale), Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Gekle
authors.affiliation: Julius-Bernstein Institute of Physiology, Martin-Luther-University of Halle-Wittenberg, Magdeburger Str. 6, 06112, Halle (Saale), Germany. oliver.thews@medizin.uni-halle.de.
authors.forename: Oliver
authors.initials: O
authors.lastname: Thews
mesh_terms: D000138:Acidosis / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D045744:Cell Line, Tumor; D003412:Cricetulus; D004285:Dogs; D006801:Humans; D006863:Hydrogen-Ion Concentration; D020935:MAP Kinase Signaling System; D061985:Madin Darby Canine Kidney Cells; D009369:Neoplasms / Q000378:metabolism*; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D059016:Tumor Microenvironment / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D048051:p38 Mitogen-Activated Protein Kinases