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Molecular Pharmacology

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Research ArticleArticle

Cross-Talk between Integrins and Oncogenes Modulates Chemosensitivity

Jordi Carreras Puigvert, Stephan Huveneers, Lisa Fredriksson, Marieke op het Veld, Bob van de Water and Erik H. J. Danen
Molecular Pharmacology April 2009, 75 (4) 947-955; DOI: https://doi.org/10.1124/mol.108.051649
Jordi Carreras Puigvert
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Stephan Huveneers
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Lisa Fredriksson
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Marieke op het Veld
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Bob van de Water
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Erik H. J. Danen
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Abstract

Chemotherapy often relies on cancer cell death resulting from DNA damage. The p53 tumor suppressor pathway that is an important player in DNA damage response is frequently inactivated in cancer. Genotoxicants also activate DNA damage-independent stress pathways and activity of oncogenic signaling and adhesive interactions with the cancer microenvironment can have a strong impact on chemosensitivity. Here, we have investigated how two different oncogenes modulate the response to genotoxicants in the context of two classes of integrin adhesion receptors. Epithelial cells expressing either β1 or β3 integrins, in which p53 activity is suppressed, undergo G2 arrest but show little apoptosis after treatment with cisplatin or other genotoxicants. The apoptotic response is strongly enhanced by the c-Src[Y530F] oncogene in cells expressing β1 integrins, whereas such sensitization is reduced when these cells are engineered to express β3 integrins instead. The H-Ras[G12V] oncogene fails to sensitize, regardless of the integrin expression profile. The enhanced sensitivity induced by c-Src[Y530F] in the context of β1 integrins does not rely on p53-mediated DNA damage signaling but instead involves increased endoplasmic reticulum stress and caspase-3 activation. Our data implicate that the expression profiles of oncogenes and integrins strongly affect the response to chemotherapeutics and may thus determine the efficacy of chemotherapy.

Footnotes

  • This work was supported by the Dutch Cancer Society [Grant UL 2003-2858] and by the Netherlands Genomics Initiative.

  • J.C.P. and S.H. contributed equally to this work.

  • ABBREVIATIONS: ECM, extracellular matrix; ER, endoplasmic reticulum; FACS, fluorescence-activated cell sorting; eIF2α, eukaryotic initiation factor 2α; z-VAD-fmk, z-Val-Ala-dl-Asp-fluoromethylketone; siRNA, small interfering RNA; DMSO, dimethyl sulfoxide; FITC, fluorescein isothiocyanate; ECL, enhanced chemiluminescence; DCVC, S-(1,2-dichlorovinyl)-l-cysteine; SID, substance accession identifier (PubChem database).

  • ↵1 Current affiliation: Hubrecht Institute, Utrecht, The Netherlands.

    • Received August 29, 2008.
    • Accepted January 15, 2009.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 75 (4)
Molecular Pharmacology
Vol. 75, Issue 4
1 Apr 2009
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Research ArticleArticle

Cross-Talk between Integrins and Oncogenes Modulates Chemosensitivity

Jordi Carreras Puigvert, Stephan Huveneers, Lisa Fredriksson, Marieke op het Veld, Bob van de Water and Erik H. J. Danen
Molecular Pharmacology April 1, 2009, 75 (4) 947-955; DOI: https://doi.org/10.1124/mol.108.051649

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Research ArticleArticle

Cross-Talk between Integrins and Oncogenes Modulates Chemosensitivity

Jordi Carreras Puigvert, Stephan Huveneers, Lisa Fredriksson, Marieke op het Veld, Bob van de Water and Erik H. J. Danen
Molecular Pharmacology April 1, 2009, 75 (4) 947-955; DOI: https://doi.org/10.1124/mol.108.051649
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