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.
Original language | English |
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Pages (from-to) | 2981-2990 |
Number of pages | 10 |
Journal | International Journal of Cancer |
Volume | 118 |
Issue number | 12 |
DOIs | |
Publication status | Published - Jun 15 2006 |
Keywords
- Apoptosis
- Cisplatin
- HGF
- p38 MAPK
- Paclitaxel
ASJC Scopus subject areas
- Cancer Research
- Oncology