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Molecular Pharmacology

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Research ArticleArticle

BCL-2 Family Inhibitors Enhance Histone Deacetylase Inhibitor and Sorafenib Lethality via Autophagy and Overcome Blockade of the Extrinsic Pathway to Facilitate Killing

Aditi Pandya Martin, Margaret A. Park, Clint Mitchell, Teneille Walker, Mohamed Rahmani, Andrew Thorburn, Dieter Häussinger, Roland Reinehr, Steven Grant and Paul Dent
Molecular Pharmacology August 2009, 76 (2) 327-341; DOI: https://doi.org/10.1124/mol.109.056309
Aditi Pandya Martin
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Margaret A. Park
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Clint Mitchell
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Teneille Walker
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Mohamed Rahmani
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Andrew Thorburn
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Dieter Häussinger
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Roland Reinehr
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Steven Grant
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Paul Dent
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Abstract

We examined whether the multikinase inhibitor sorafenib and histone deacetylase inhibitors (HDACI) interact to kill pancreatic carcinoma cells and determined the impact of inhibiting BCL-2 family function on sorafenib and HDACI lethality. The lethality of sorafenib was enhanced in pancreatic tumor cells in a synergistic fashion by pharmacologically achievable concentrations of the HDACIs vorinostat or sodium valproate. Overexpression of cellular FLICE-like inhibitory protein (c-FLIP-s) or knockdown of CD95 suppressed the lethality of the sorafenib/HDACI combination (sorafenib + HDACI). In immunohistochemical analyses or using expression of fluorescence-tagged proteins, treatment with sorafenib and vorinostat together (sorafenib + vorinostat) promoted colocalization of CD95 with caspase 8 and CD95 association with the endoplasmic reticulum markers calnexin, ATG5, and Grp78/BiP. In cells lacking CD95 expression or in cells expressing c-FLIP-s, the lethality of sorafenib + HDACI exposure was abolished and was restored when cells were coexposed to BCL-2 family inhibitors [ethyl [2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)]-4H-chromene-3-carboxylate (HA14-1), obatoclax (GX15-070)]. Knockdown of BCL-2, BCL-XL, and MCL-1 recapitulated the effects of GX15-070 treatment. Knockdown of BAX and BAK modestly reduced sorafenib + HDACI lethality but abolished the effects of GX15-070 treatment. Sorafenib + HDACI exposure generated a CD95- and Beclin1-dependent protective form of autophagy, whereas GX15-070 treatment generated a Beclin1-dependent toxic form of autophagy. The potentiation of sorafenib + HDACI killing by GX15-070 was suppressed by knockdown of Beclin1 or of BAX + BAK. Our data demonstrate that pancreatic tumor cells are susceptible to sorafenib + HDACI lethality and that in tumor cells unable to signal death from CD95, use of a BCL-2 family antagonist facilitates sorafenib + HDACI killing via autophagy and the intrinsic pathway.

Footnotes

  • This work was funded by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant R01-DK52825]; the National Institutes of Health National Cancer Institute [Grants P01-CA104177, R01-CA108520, R01-CA63753, R01-CA77141; R01-CA93738]; by The Jimmy V Foundation; and by The Goodwin Foundation for Cancer Research (to Massey Cancer Center). P.D. is the holder of the Universal Inc. Professorship in Signal Transduction Research.

  • A.P.M., M.A.P., and C.M. contributed equally to this work.

  • ABBREVIATIONS: MEK, mitogen-activated extracellular-regulated kinase; ERK, extracellular regulated kinase; MAPK, mitogen-activated protein kinase; JNK, c-Jun NH2-terminal kinase; c-FLIP-s, cellular FLICE-like inhibitory protein; ER, endoplasmic reticulum; dn, dominant negative; ca, constitutively active; PERK, PKR-like endoplasmic reticulum kinase; PKR, protein kinase regulated by RNA; HDACI, histone deacetylase inhibitor; GX15-070; HA14-1; TUNEL, terminal deoxynucleotidyl transferase dUTP nick-end labeling; GFP, green fluorescent protein; YFP, yellow fluorescent protein; DMSO, dimethyl sulfoxide; PAGE, polyacrylamide gel electrophoresis; FITC, fluorescein isothiocyanate; PE, phycoerythrin; CMV, cytomegalovirus; siRNA, small interfering RNA; siSCR, scrambled siRNA; DISC, death-inducing signal complex; FADD, FAS-associated death domain; IHC, immunohistochemistry; MEF, mouse embryonic fibroblast.

  • ↵ Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

    • Accepted May 29, 2009.
    • Received March 18, 2009.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 76 (2)
Molecular Pharmacology
Vol. 76, Issue 2
1 Aug 2009
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Research ArticleArticle

BCL-2 Family Inhibitors Enhance Histone Deacetylase Inhibitor and Sorafenib Lethality via Autophagy and Overcome Blockade of the Extrinsic Pathway to Facilitate Killing

Aditi Pandya Martin, Margaret A. Park, Clint Mitchell, Teneille Walker, Mohamed Rahmani, Andrew Thorburn, Dieter Häussinger, Roland Reinehr, Steven Grant and Paul Dent
Molecular Pharmacology August 1, 2009, 76 (2) 327-341; DOI: https://doi.org/10.1124/mol.109.056309

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Research ArticleArticle

BCL-2 Family Inhibitors Enhance Histone Deacetylase Inhibitor and Sorafenib Lethality via Autophagy and Overcome Blockade of the Extrinsic Pathway to Facilitate Killing

Aditi Pandya Martin, Margaret A. Park, Clint Mitchell, Teneille Walker, Mohamed Rahmani, Andrew Thorburn, Dieter Häussinger, Roland Reinehr, Steven Grant and Paul Dent
Molecular Pharmacology August 1, 2009, 76 (2) 327-341; DOI: https://doi.org/10.1124/mol.109.056309
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