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

Research output: Contribution to journalArticlepeer-review

Authors

  • Nadia Coltella
  • Andrea Rasola
  • Elisa Nano
  • Michela Fassetta
  • Nicoletta Filigheddu
  • Andrea Graziani
  • Paolo M Comoglio
  • Maria Flavia Di Renzo

Colleges, School and Institutes

External organisations

  • University of Turin

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.

Details

Original languageEnglish
Pages (from-to)2981-90
Number of pages10
JournalInternational Journal of Cancer
Volume118
Issue number12
Publication statusPublished - 15 Jun 2006

Keywords

  • Adenocarcinoma/drug therapy, Annexin A5/metabolism, Antineoplastic Combined Chemotherapy Protocols/pharmacology, Apoptosis/drug effects, Cell Line, Tumor, Chromones/pharmacology, Cisplatin/pharmacology, Female, Flavonoids/pharmacology, Flow Cytometry, Fluorescein-5-isothiocyanate, Gene Expression Regulation, Neoplastic, Hepatocyte Growth Factor/metabolism, Humans, MAP Kinase Kinase 4/metabolism, MAP Kinase Signaling System/drug effects, Mitogen-Activated Protein Kinase 3/metabolism, Morpholines/pharmacology, Ovarian Neoplasms/drug therapy, Paclitaxel/pharmacology, Protein Kinase Inhibitors/pharmacology, Rhodamines/pharmacology, p38 Mitogen-Activated Protein Kinases/metabolism

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