Received for publication March 28, 2006.
Revised April 16, 2006.
Accepted for publication April 18, 2006.

OSU-03012 promotes caspase-independent, PERK-, cathepsin B-, BID- and AIF-dependent killing of transformed cells

Abstract

We determined one mechanism by which the putative PDK-1 inhibitor OSU-03012 (OSU) killed primary human glioma and other transformed cells. OSU caused a dose-dependent induction of cell death that was not altered by p53 mutation, expression of ERBB1 vIII, or loss of PTEN function. OSU promoted cell killing to a greater extent in glioma cells than in non-transformed astrocytes. OSU and ionizing radiation caused an additive, caspase-independent, elevation in cell killing in 96h viability assays and true radiosensitization in colony formation assays. In a cell type-specific manner combined exposure to OSU with a MEK1/2 inhibitor, PI3K/AKT inhibitors or parallel molecular interventions resulted in a greater than additive induction of cell killing that was independent of AKT activity and caspase function. OSU lethality as a single agent or when combined with signaling modulators was not modified in cells lacking expression of BIM or of BAX/BAK. OSU promoted the release of cathepsin B from the lysosomal compartment and release of AIF from mitochondria. Loss of BID function, over-expression of BCL-_XL, and inhibition of cathepsin B function, suppressed cell killing and AIF release from mitochondria. In PERK -/- cells the lethality of OSU was attenuated which correlated with reduced cleavage of BID and with suppression of cathepsin B and AIF release into the cytosol. Our data demonstrate that OSU-03012 promotes glioma cell killing that is dependent on ER stress, lysosomal dysfunction and BID-dependent release of AIF from mitochondria, and whose lethality is enhanced by irradiation or by inhibition of protective signaling pathways.

Key words: Protein Kinases (other), MAP Kinase, Apoptosis, Oxidative stress/antioxidants, Mechanisms of cell killing/apoptosis

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