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Research ArticleArticle

OSU-03012 Promotes Caspase-Independent but PERK-, Cathepsin B-, BID-, and AIF-Dependent Killing of Transformed Cells

Adly Yacoub, Margaret A. Park, David Hanna, Young Hong, Clint Mitchell, Aditi P. Pandya, Hisashi Harada, Garth Powis, Ching-Shih Chen, Costas Koumenis, Steven Grant and Paul Dent
Molecular Pharmacology August 2006, 70 (2) 589-603; DOI: https://doi.org/10.1124/mol.106.025007
Adly Yacoub
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Margaret A. Park
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David Hanna
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Young Hong
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Clint Mitchell
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Aditi P. Pandya
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Hisashi Harada
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Garth Powis
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Ching-Shih Chen
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Costas Koumenis
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Steven Grant
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Paul Dent
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Abstract

We determined one mechanism by which the putative phosphoinositide-dependent kinase (PDK)-1 inhibitor 2-amino-N-{4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-phenyl}acetamide (OSU-03012) killed primary human glioma and other transformed cells. OSU-03012 caused a dose-dependent induction of cell death that was not altered by p53 mutation, expression of ERBB1 vIII, or loss of phosphatase and tensin homolog deleted on chromosome 10 function. OSU-03012 promoted cell killing to a greater extent in glioma cells than in nontransformed astrocytes. OSU-03012 and ionizing radiation caused an additive, caspase-independent elevation in cell killing in 96-h viability assays and true radiosensitization in colony formation assays. In a cell type-specific manner, combined exposure to OSU-03012 with a mitogen-activated protein kinase kinase 1/2 inhibitor, phosphoinositide 3-kinase/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-03012 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-03012 promoted the release of cathepsin B from the lysosomal compartment and release of AIF from mitochondria. Loss of BH3-interacting domain (BID) function, overexpression of BCLXL, and inhibition of cathepsin B function suppressed cell killing and apoptosis-inducing factor (AIF) release from mitochondria. In protein kinase R-like endoplasmic reticulum kinase-/- cells, the lethality of OSU-03012 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 endoplasmic reticulum 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.

  • Received March 28, 2006.
  • Accepted April 18, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 70 (2)
Molecular Pharmacology
Vol. 70, Issue 2
1 Aug 2006
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Research ArticleArticle

OSU-03012 Promotes Caspase-Independent but PERK-, Cathepsin B-, BID-, and AIF-Dependent Killing of Transformed Cells

Adly Yacoub, Margaret A. Park, David Hanna, Young Hong, Clint Mitchell, Aditi P. Pandya, Hisashi Harada, Garth Powis, Ching-Shih Chen, Costas Koumenis, Steven Grant and Paul Dent
Molecular Pharmacology August 1, 2006, 70 (2) 589-603; DOI: https://doi.org/10.1124/mol.106.025007

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Research ArticleArticle

OSU-03012 Promotes Caspase-Independent but PERK-, Cathepsin B-, BID-, and AIF-Dependent Killing of Transformed Cells

Adly Yacoub, Margaret A. Park, David Hanna, Young Hong, Clint Mitchell, Aditi P. Pandya, Hisashi Harada, Garth Powis, Ching-Shih Chen, Costas Koumenis, Steven Grant and Paul Dent
Molecular Pharmacology August 1, 2006, 70 (2) 589-603; DOI: https://doi.org/10.1124/mol.106.025007
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