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

Int J Cancer. 2006 Jun 15;118(12):2981-90. doi: 10.1002/ijc.21766.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / enzymology
  • Adenocarcinoma / metabolism*
  • Adenocarcinoma / pathology
  • 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
  • Ovarian Neoplasms / enzymology
  • Ovarian Neoplasms / metabolism*
  • Ovarian Neoplasms / pathology
  • Paclitaxel / pharmacology
  • Protein Kinase Inhibitors / pharmacology
  • Rhodamines / pharmacology
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • Annexin A5
  • Chromones
  • Flavonoids
  • Morpholines
  • Protein Kinase Inhibitors
  • Rhodamines
  • tetramethylrhodamine methyl ester
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Hepatocyte Growth Factor
  • Mitogen-Activated Protein Kinase 3
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 4
  • Fluorescein-5-isothiocyanate
  • Paclitaxel
  • Cisplatin
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one