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Research ArticleArticle

Poly(ADP-Ribose) Polymerase 1 Modulates the Lethality of CHK1 Inhibitors in Carcinoma Cells

Clint Mitchell, Margaret Park, Patrick Eulitt, Chen Yang, Adly Yacoub and Paul Dent
Molecular Pharmacology November 2010, 78 (5) 909-917; DOI: https://doi.org/10.1124/mol.110.067199
Clint Mitchell
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Margaret Park
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Patrick Eulitt
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Chen Yang
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Adly Yacoub
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Paul Dent
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This article has a correction. Please see:

  • Correction to “Poly(ADP-Ribose) Polymerase 1 Modulates the Lethality of CHK1 Inhibitors in Carcinoma Cells” - January 01, 2011

Abstract

Prior studies have demonstrated that inhibition of CHK1 can promote the activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and phosphorylation of histone H2AX and that inhibition of poly(ADP-ribose) polymerase 1 (PARP1) can affect growth factor-induced ERK1/2 activation. The present studies were initiated to determine whether CHK1 inhibitors interacted with PARP1 inhibition to facilitate apoptosis. Transient expression of dominant-negative CHK1 raised basal ERK1/2 activity and prevented CHK1 inhibitors from activating ERK1/2. CHK1 inhibitors modestly increased the levels of PARP1 ADP ribosylation and molecular or small-molecule inhibition of PARP1 blocked CHK1 inhibitor-stimulated histone H2AX phosphorylation and activation of ERK1/2. Stimulated histone H2AX phosphorylation was ataxia telangiectasia-mutated protein-dependent. Multiple CHK1 inhibitors interacted in a greater than additive fashion with multiple PARP1 inhibitors to cause transformed cell-killing in short-term viability assays and synergistically killed tumor cells in colony-formation assays. Overexpression of BCL-xL or loss of BAX/BAK function, but not the function of BID, suppressed CHK1 inhibitor + PARP1 inhibitor lethality. Inhibition of BCL-2 family protein function enhanced CHK1 inhibitor + PARP1 inhibitor lethality and restored drug-induced cell-killing in cells overexpressing BCL-xL. Thus, PARP1 plays an important role in regulating the ability of CHK1 inhibitors to activate ERK1/2 and the DNA damage response. An inability of PARP1 to modulate this response results in transformed cell death mediated through the intrinsic apoptosis 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-CA108325; R01-CA150214]; Department of Defense Awards [Grants DAMD17-03-1-0262; W81XWH-10-1-0009]; The Jim Valvano “Jimmy V” Foundation; The Goodwin Foundation; and the Universal Inc. Professorship in Signal Transduction Research (P.D.).

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

    doi:10.1124/mol.110.067199.

  • ABBREVIATIONS:

    UCN-01
    7-hydroxystaurosporine
    ERK
    extracellular signal-regulated kinase
    MEK
    mitogen-activated protein kinase kinase
    m.o.i.
    multiplicity of infection
    DMSO
    dimethyl sulfoxide
    ATM
    ataxia telangiectasia-mutated
    PAGE
    polyacrylamide gel electrophoresis
    CI
    combination index
    FBS
    fetal bovine serum
    GAPDH
    glyceraldehyde-3-phosphate dehydrogenase
    siRNA
    small interfering RNA
    PARP1
    poly(ADP-ribose) polymerase 1
    AZD7762
    5-(3-fluoro-phenyl)-3-ureido-thiophene-2-carboxylic acid (S)-piperidin-3-ylamide hydrochloride
    GPI15427
    10-(4-methyl-piperazin-1-ylmethyl)-2H-7-oxa-1,2-diaza-benzo[de]anthracen-3-one
    NU1025
    8-hydroxy-2-methyl-4(3H)-quinazolinone
    AZD2281
    olaparib
    EE
    [Glu218,Glu222]Mek1
    PD184352
    2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-benzamide
    PD98059
    2′-amino-3′-methoxyflavone
    PJ34
    N-(5,6-dihydro-6-oxo-2-phenanthridinyl)-2-acetamide hydrochloride
    AG1478
    4-(3′-chloroanilino)-6,7-dimethoxy-quinazoline
    GX15-070
    obatoclax
    ABT888
    veliparib
    HA14-1
    2-amino-6-bromo-a-cyano-3-(ethoxycarbonyl)-4H-1-benzopy ran-4-acetic acid ethyl ester
    ABT-263
    navitoclax
    KU55933
    2-(4-morpholinyl)-6-(1-thianthrenyl)-4H-pyran-4-one
    CEP6800
    10-(aminomethyl)-4,5,6,7-tetrahydro-1H-cyclopenta[a]pyrrolo[3,4-c]carbazole-1,3(2H)-dione.

  • Received June 29, 2010.
  • Accepted August 9, 2010.
  • Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 78 (5)
Molecular Pharmacology
Vol. 78, Issue 5
1 Nov 2010
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Research ArticleArticle

Poly(ADP-Ribose) Polymerase 1 Modulates the Lethality of CHK1 Inhibitors in Carcinoma Cells

Clint Mitchell, Margaret Park, Patrick Eulitt, Chen Yang, Adly Yacoub and Paul Dent
Molecular Pharmacology November 1, 2010, 78 (5) 909-917; DOI: https://doi.org/10.1124/mol.110.067199

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Research ArticleArticle

Poly(ADP-Ribose) Polymerase 1 Modulates the Lethality of CHK1 Inhibitors in Carcinoma Cells

Clint Mitchell, Margaret Park, Patrick Eulitt, Chen Yang, Adly Yacoub and Paul Dent
Molecular Pharmacology November 1, 2010, 78 (5) 909-917; DOI: https://doi.org/10.1124/mol.110.067199
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