title: PtdIns5P is an oxidative stress-induced second messenger that regulates PKB activation.
abstract: Oxidative stress initiates signaling pathways, which protect from stress-induced cellular damage, initiate apoptosis, or drive cells into senescence or into tumorigenesis. Oxidative stress regulates the activity of the cell survival factor PKB, through the regulation of PtdIns(3,4,5)P₃ synthesis. Whether oxidative stress regulates other phosphoinositides to control PKB activation is not clear. Here we show that PtdIns5P is a redox-regulated second messenger. In response to hydrogen peroxide (H₂O₂), we measured an increase in PtdIns5P in cells derived from human osteosarcoma, U2OS (5-fold); breast tumors, MDA-MB-468 (2-fold); and fibrosarcoma, HT1080 (3-fold); and in p53-null murine embryonic fibroblasts (8-fold). In U2OS cells, the increase in H₂O₂-dependent PtdIns5P did not require mTOR, PDK1, PKB, ERK, and p38 signaling or PIKfyve, a lipid kinase that increases PtdIns5P in response to osmotic and oncogenic signaling. A reduction in H₂O₂-induced PtdIns5P levels by the overexpression of PIP4K revealed its role in PKB activation. Suppression of H₂O₂-induced PtdIns5P generation reduced PKB activation and, surprisingly, reduced cell sensitivity to growth inhibition by H₂O₂. These data suggest that inhibition of PIP4K signaling might be useful as a novel strategy to increase the susceptibility of tumor cells to therapeutics that function through increased oxidative stress.
authors.affiliation: Cancer Research UK Inositide Laboratory, The Paterson Institute for Cancer Research, University of Manchester, Manchester, UK.
authors.forename: David R
authors.initials: DR
authors.lastname: Jones
authors.forename: Rebecca
authors.initials: R
authors.lastname: Foulger
authors.forename: Willem-Jan
authors.initials: WJ
authors.lastname: Keune
authors.forename: Yvette
authors.initials: Y
authors.lastname: Bultsma
authors.forename: Nullin
authors.initials: N
authors.lastname: Divecha
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004789:Enzyme Activation; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015290:Second Messenger Systems / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D018129:Phosphatidylinositol Phosphates; C113567:phosphatidylinositol 5-phosphate; D006861:Hydrogen Peroxide; D064413:3-Phosphoinositide-Dependent Protein Kinases; C578562:PDPK1 protein, human; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases