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Molecular Pharmacology

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Research ArticleArticle

Sorafenib and Vorinostat Kill Colon Cancer Cells by CD95-Dependent and -Independent Mechanisms

Teneille Walker, Clint Mitchell, Margaret A. Park, Adly Yacoub, Martin Graf, Mohamed Rahmani, Peter J. Houghton, Christina Voelkel-Johnson, Steven Grant and Paul Dent
Molecular Pharmacology August 2009, 76 (2) 342-355; DOI: https://doi.org/10.1124/mol.109.056523
Teneille Walker
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Clint Mitchell
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Margaret A. Park
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Adly Yacoub
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Martin Graf
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Mohamed Rahmani
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Peter J. Houghton
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Christina Voelkel-Johnson
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Steven Grant
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Abstract

We examined the interaction between the multikinase inhibitor sorafenib and histone deacetylase inhibitors. Sorafenib and vorinostat synergized (sorafenib + vorinostat) to kill HCT116 and SW480 cells. In SW480 cells, sorafenib + vorinostat increased CD95 plasma membrane levels and promoted death-inducing signal complex (DISC) formation, and drug toxicity was blocked by knockdown of CD95 or overexpression of cellular FLICE-like inhibitory protein (c-FLIP-s). In SW620 cells that are patient-matched to SW480 cells, sorafenib + vorinostat toxicity was significantly lower, which correlated with a lack of CD95 activation and lower expression of ceramide synthase 6 (LASS6). Overexpression of LASS6 in SW620 cells enhanced drug-induced CD95 activation and enhanced tumor cell killing, whereas knockdown of LASS6 in SW480 cells suppressed CD95 activation. Knocking down LASS6 expression also suppressed CD95 activation in hepatoma, pancreatic, and ovarian cancer cells. In HCT116 cells, sorafenib + vorinostat treatment caused DISC formation without reducing c-FLIP-s expression and did not increase CD95 plasma membrane levels; sorafenib + vorinostat exposure killed HCT116 cells via an intrinsic pathway/caspase 9-dependent mechanism. In HCT116 cells, knockdown of CD95 enhanced sorafenib + vorinostat lethality, which correlated with less drug-induced CD95-dependent autophagy. Sorafenib + vorinostat treatment activated the c-Jun NH2-terminal kinase pathway, which was causal in promoting dissociation of Beclin1 from BCL-2, and in promoting autophagy. Knockdown of Beclin1 expression blocked autophagy and enhanced drug toxicity. Our data demonstrate that treatment of colon cancer cells with sorafenib + vorinostat activates CD95 via de novo ceramide synthesis that promotes viability via autophagy or degrades survival via either the extrinsic or intrinsic pathways.

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.

  • ABBREVIATIONS: MEK, mitogen activated extracellular regulated kinase; ERK, extracellular regulated kinase; JNK, c-Jun NH2-terminal kinase; MAPK, mitogen activated protein kinase; c-FLIP, cellular FLICE-like inhibitory protein; PERK, protein kinase-like endoplasmic reticulum kinase; ER, endoplasmic reticulum; PI3K, phosphatidyl inositol 3 kinase; MCL-1, myeloid cell leukemia sequence 1 (BCL2-related); HDACI, histone deacetylase inhibitor; CMV, cytomegalovirus; DMSO, dimethyl sulfoxide; GX15-070, obatoclax; dn, dominant negative; CI, combination index; DISC, death-inducing signal complex; ASMase, acidic sphingomyelinase; LASS6, ceramide synthase 6; eIF2α, eukaryotic initiation factor 2α; BCL-2, B-cell lymphoma 2; FITC, fluorescein isothiocyanate; PAGE, polyacrylamide gel electrophoresis; siSCR, scrambled siRNA.

    • Accepted May 27, 2009.
    • Received March 25, 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

Sorafenib and Vorinostat Kill Colon Cancer Cells by CD95-Dependent and -Independent Mechanisms

Teneille Walker, Clint Mitchell, Margaret A. Park, Adly Yacoub, Martin Graf, Mohamed Rahmani, Peter J. Houghton, Christina Voelkel-Johnson, Steven Grant and Paul Dent
Molecular Pharmacology August 1, 2009, 76 (2) 342-355; DOI: https://doi.org/10.1124/mol.109.056523

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Research ArticleArticle

Sorafenib and Vorinostat Kill Colon Cancer Cells by CD95-Dependent and -Independent Mechanisms

Teneille Walker, Clint Mitchell, Margaret A. Park, Adly Yacoub, Martin Graf, Mohamed Rahmani, Peter J. Houghton, Christina Voelkel-Johnson, Steven Grant and Paul Dent
Molecular Pharmacology August 1, 2009, 76 (2) 342-355; DOI: https://doi.org/10.1124/mol.109.056523
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