p38 MAPK turns hepatocyte growth factor to a death signal that commits ovarian cancer cells to chemotherapy-induced apoptosis

Authors

  • Nadia Coltella,

    1. Laboratory of Cancer Genetics, Institute for Cancer Research and Treatment, University of Turin Medical School, Candiolo (Turin) Italy
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    • The first 2 authors contributed equally to this work

  • Andrea Rasola,

    1. Division of Molecular Oncology of the Institute for Cancer Research and Treatment (IRCC), University of Turin Medical School, Candiolo (Turin) Italy
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    • The first 2 authors contributed equally to this work

  • Elisa Nano,

    1. Laboratory of Cancer Genetics, Institute for Cancer Research and Treatment, University of Turin Medical School, Candiolo (Turin) Italy
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  • Chiara Bardella,

    1. Laboratory of Cancer Genetics, Institute for Cancer Research and Treatment, University of Turin Medical School, Candiolo (Turin) Italy
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  • Michela Fassetta,

    1. Division of Molecular Oncology of the Institute for Cancer Research and Treatment (IRCC), University of Turin Medical School, Candiolo (Turin) Italy
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  • Nicoletta Filigheddu,

    1. Department of Medical Sciences, University Amedeo Avogadro of Piemonte Orientale, Novara, Italy
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  • Andrea Graziani,

    1. Department of Medical Sciences, University Amedeo Avogadro of Piemonte Orientale, Novara, Italy
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  • Paolo M. Comoglio,

    1. Division of Molecular Oncology of the Institute for Cancer Research and Treatment (IRCC), University of Turin Medical School, Candiolo (Turin) Italy
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  • Maria Flavia Di Renzo

    Corresponding author
    1. Laboratory of Cancer Genetics, Institute for Cancer Research and Treatment, University of Turin Medical School, Candiolo (Turin) Italy
    • Laboratory of Cancer Genetics of the Institute for Cancer Research and Treatment (IRCC), University of Turin Medical School, SP 142, KM 3.95, 10060, Candiolo (Torino), Italy
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    • Fax: +39-011-993-3524.


Abstract

We recently showed that Hepatocyte Growth Factor (HGF), known as a survival factor, unexpectedly enhances apoptosis in human ovarian cancer cells treated with the front-line chemotherapeutics cisplatin (CDDP) and paclitaxel (PTX). Here we demonstrate that this effect depends on the p38 mitogen-activated kinase (MAPK). In fact, p38 MAPK activity is stimulated by HGF and further increased by the combined treatment with HGF and either CDDP or PTX. The expression of a dominant negative form of p38 MAPK abrogates apoptosis elicited by drugs, alone or in combination with HGF. HGF and drugs also activate the ERK1/2 MAPKs, the PI3K/AKT and the AKT substrate mTOR. However, activation of these survival pathways does not hinder the ability of HGF to enhance drug-dependent apoptosis. Altogether data show that p38 MAPK is necessary for HGF sensitization of ovarian cancer cells to low-doses of CDDP and PTX and might be sufficient to overcome activation of survival pathways. Therefore, the p38 MAPK pathway might be a suitable target to improve response to conventional chemotherapy in human ovarian cancer. © 2006 Wiley-Liss, Inc.

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