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 H2O 2-induced PtdIns5P generation reduced PKB activation and, surprisingly, reduced cell sensitivity to growth inhibition by H 2O2. 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.
Original language | English |
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Pages (from-to) | 1644-1656 |
Number of pages | 12 |
Journal | Faseb Journal |
Volume | 27 |
Issue number | 4 |
DOIs | |
Publication status | Published - Apr 2013 |
Keywords
- Lipid kinase
- Phosphatidylinositol-5-phosphate kinase
- Phosphoinositide
Research Beacons, Institutes and Platforms
- Manchester Cancer Research Centre