Premium
p38 MAPK turns hepatocyte growth factor to a death signal that commits ovarian cancer cells to chemotherapy‐induced apoptosis
Author(s) -
Coltella Nadia,
Rasola Andrea,
Nano Elisa,
Bardella Chiara,
Fassetta Michela,
Filigheddu Nicoletta,
Graziani Andrea,
Comoglio Paolo M.,
Di Renzo Maria Flavia
Publication year - 2006
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.21766
Subject(s) - hepatocyte growth factor , mapk/erk pathway , cancer research , ovarian cancer , protein kinase b , cisplatin , paclitaxel , apoptosis , p38 mitogen activated protein kinases , pi3k/akt/mtor pathway , c met , medicine , chemotherapy , kinase , cancer , biology , microbiology and biotechnology , receptor , biochemistry
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.