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Research ArticleArticle

Cisplatin Enhances Protein Kinase R-Like Endoplasmic Reticulum Kinase- and CD95-Dependent Melanoma Differentiation-Associated Gene-7/Interleukin-24–Induced Killing in Ovarian Carcinoma Cells

Adly Yacoub, Renyan Liu, Margaret A. Park, Hossein A. Hamed, Rupesh Dash, Danielle N. Schramm, Devanand Sarkar, Igor P. Dimitriev, Jessica K. Bell, Steven Grant, Nicholas P. Farrell, David T. Curiel, Paul B. Fisher and Paul Dent
Molecular Pharmacology February 2010, 77 (2) 298-310; DOI: https://doi.org/10.1124/mol.109.061820
Adly Yacoub
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Renyan Liu
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Margaret A. Park
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Hossein A. Hamed
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Rupesh Dash
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Danielle N. Schramm
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Devanand Sarkar
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Igor P. Dimitriev
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Jessica K. Bell
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Steven Grant
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Nicholas P. Farrell
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David T. Curiel
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Paul B. Fisher
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Paul Dent
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Abstract

Melanoma differentiation associated gene-7/interleukin 24 (mda-7/IL-24) is a unique interleukin (IL)-10 family cytokine displaying selective apoptosis-inducing activity in transformed cells without harming normal cells. The present studies focused on defining the mechanism(s) by which recombinant adenoviral delivery of MDA-7/IL-24 inhibits cell survival of human ovarian carcinoma cells. Expression of MDA-7/IL-24 induced phosphorylation of protein kinase R-like endoplasmic reticulum kinase (PERK) and eukaryotic initiation factor2α (eIF2α). In a PERK-dependent fashion, MDA-7/IL-24 reduced ERK1/2 and AKT phosphorylation and activated c-Jun NH2-terminal kinase (JNK) 1/2 and p38 mitogen-activated protein kinase (MAPK). MDA-7/IL-24 reduced MCL-1 and BCL-XL and increased BAX levels via PERK signaling; cell-killing was mediated via the intrinsic pathway, and cell killing was primarily necrotic as judged using Annexin V/propidium iodide staining. Inhibition of p38 MAPK and JNK1/2 abolished MDA-7/IL-24 toxicity and blocked BAX and BAK activation, whereas activation of mitogen-activated extracellular-regulated kinase (MEK) 1/2 or AKT suppressed enhanced killing and JNK1/2 activation. MEK1/2 signaling increased expression of the MDA-7/IL-24 and PERK chaperone BiP/78-kDa glucose regulated protein (GRP78), and overexpression of BiP/GRP78 suppressed MDA-7/IL-24 toxicity. MDA-7/IL-24-induced LC3-green fluorescent protein vesicularization and processing of LC3; and knockdown of ATG5 suppressed MDA-7/IL-24-mediated toxicity. MDA-7/IL-24 and cisplatin interacted in a greater than additive fashion to kill tumor cells that was dependent on a further elevation of JNK1/2 activity and recruitment of the extrinsic CD95 pathway. MDA-7/IL-24 toxicity was enhanced in a weak additive fashion by paclitaxel; paclitaxel enhanced MDA-7/IL-24 + cisplatin lethality in a greater than additive fashion via BAX. Collectively, our data demonstrate that MDA-7/IL-24 induces an endoplasmic reticulum stress response that activates multiple proapoptotic pathways, culminating in decreased ovarian tumor cell survival.

Footnotes

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

  • This work was supported by the National Institutes of Health National Cancer Institute [Grants P01-CA104177, R01-CA108325, R01-CA63753, R01-CA77141, R01-CA097318, R01-CA12764101]; the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant R01-DK52825]; the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant P01-NS031492]; the V Foundation; and The Samuel Waxman Cancer Research Foundation.

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.109.061820

  • ABBREVIATIONS:

    MDA-7/IL-24
    melanoma differentiation associated gene-7/interleukin-24
    ERK
    extracellular signal-regulated kinase
    MEK
    mitogen-activated extracellular regulated kinase
    JNK
    c-Jun NH2-terminal kinase
    PERK
    protein kinase R-like endoplasmic reticulum kinase
    MAPK
    mitogen-activated protein kinase
    IL
    interleukin
    OCC
    ovarian cancer cell
    GFP
    green fluorescent protein
    ER
    endoplasmic reticulum
    GST
    glutathione transferase
    PAGE
    polyacrylamide gel electrophoresis
    m.o.i.
    multiplicity of infection
    CDDP
    cisplatin [cis-diamminedichloroplatinum(II)]
    FBS
    fetal bovine serum
    GBM
    glioblastoma
    GRP78
    78-kDa glucose regulated protein
    PARP1
    poly(ADP-ribose) polymerase 1
    siRNA
    small interfering RNA
    IP
    inhibitory peptide
    GAPDH
    glyceraldehyde-3-phosphate dehydrogenase
    MCL-1
    myeloid cell leukemia sequence 1
    IRE1
    inositol requirement 1
    BBR3464
    (SP-4–1)-diamminebis((SP-4–2)-diamminechloroplatinum(π) (μ-hexane-1,6-diamine))platinum tetranitrate
    LY294002
    2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride
    eIF2α
    eukaryotic initiation factor 2α.

  • Received October 20, 2009.
  • Accepted November 11, 2009.
  • Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 77 (2)
Molecular Pharmacology
Vol. 77, Issue 2
1 Feb 2010
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Research ArticleArticle

Cisplatin Enhances Protein Kinase R-Like Endoplasmic Reticulum Kinase- and CD95-Dependent Melanoma Differentiation-Associated Gene-7/Interleukin-24–Induced Killing in Ovarian Carcinoma Cells

Adly Yacoub, Renyan Liu, Margaret A. Park, Hossein A. Hamed, Rupesh Dash, Danielle N. Schramm, Devanand Sarkar, Igor P. Dimitriev, Jessica K. Bell, Steven Grant, Nicholas P. Farrell, David T. Curiel, Paul B. Fisher and Paul Dent
Molecular Pharmacology February 1, 2010, 77 (2) 298-310; DOI: https://doi.org/10.1124/mol.109.061820

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Research ArticleArticle

Cisplatin Enhances Protein Kinase R-Like Endoplasmic Reticulum Kinase- and CD95-Dependent Melanoma Differentiation-Associated Gene-7/Interleukin-24–Induced Killing in Ovarian Carcinoma Cells

Adly Yacoub, Renyan Liu, Margaret A. Park, Hossein A. Hamed, Rupesh Dash, Danielle N. Schramm, Devanand Sarkar, Igor P. Dimitriev, Jessica K. Bell, Steven Grant, Nicholas P. Farrell, David T. Curiel, Paul B. Fisher and Paul Dent
Molecular Pharmacology February 1, 2010, 77 (2) 298-310; DOI: https://doi.org/10.1124/mol.109.061820
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