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  • Phospholipase D2 mediates survival signaling through direct regulation of Akt in glioblastoma cells.

Phospholipase D2 mediates survival signaling through direct regulation of Akt in glioblastoma cells.

The Journal of biological chemistry (2013-11-22)
Ronald C Bruntz, Harry E Taylor, Craig W Lindsley, H Alex Brown
ZUSAMMENFASSUNG

The lack of innovative drug targets for glioblastoma multiforme (GBM) limits patient survival to approximately 1 year following diagnosis. The pro-survival kinase Akt provides an ideal target for the treatment of GBM as Akt signaling is frequently activated in this cancer type. However, the central role of Akt in physiological processes limits its potential as a therapeutic target. In this report, we show that the lipid-metabolizing enzyme phospholipaseD(PLD) is a novel regulator of Akt inGBM.Studies using a combination of small molecule PLD inhibitors and siRNA knockdowns establish phosphatidic acid, the product of the PLD reaction, as an essential component for the membrane recruitment and activation of Akt. Inhibition of PLD enzymatic activity and subsequent Akt activation decreases GBM cell viability by specifically inhibiting autophagic flux. We propose a mechanism whereby phosphorylation of beclin1 by Akt prevents binding of Rubicon (RUN domain cysteine-rich domain containing beclin1-interacting protein), an interaction known to inhibit autophagic flux. These findings provide a novel framework through which Akt inhibition can be achieved without directly targeting the kinase.

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Sigma-Aldrich
Phospholipase D aus Streptomyces chromofuscus, ≥50,000 units/mL, buffered aqueous glycerol solution
Sigma-Aldrich
Phospholipase D aus Kohl, Type IV, lyophilized powder, ≥100 units/mg solid
Sigma-Aldrich
Phospholipase D from Streptomyces sp., Type VII, lyophilized powder, ≥150 units/mg solid
Sigma-Aldrich
Phospholipase D from Arachis hypogaea (peanut), Type II, lyophilized powder, ≥60 units/mg protein
Avanti
Inositol Snoopers, Avanti Research - A Croda Brand 330500
Avanti
VU0359595, (1R,2R)-N-([S]-1-{4-[5-bromo-2-oxo-2,3-dihydro-1H-benzo(d)imidazol-1-yl]piperidin-1-yl}propan-2-yl)-2-phenylcyclopropanecarboxamide, powder