p38 MAPK turns hepatocyte growth factor to a death signal that commits ovarian cancer cells to chemotherapy-induced apoptosis.
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.
Coltella
Nadia
N
Laboratory of Cancer Genetics, Institute for Cancer Research and Treatment, University of Turin Medical School, Candiolo, Italy.
Rasola
Andrea
A
Nano
Elisa
E
Bardella
Chiara
C
Fassetta
Michela
M
Filigheddu
Nicoletta
N
Graziani
Andrea
A
Comoglio
Paolo M
PM
Di Renzo
Maria Flavia
MF
D000230:Adenocarcinoma / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D017304:Annexin A5 / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D002945:Cisplatin / Q000494:pharmacology; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D005434:Flow Cytometry; D016650:Fluorescein-5-isothiocyanate; D015972:Gene Expression Regulation, Neoplastic; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012235:Rhodamines / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D017304:Annexin A5; D002867:Chromones; D005419:Flavonoids; D009025:Morpholines; D047428:Protein Kinase Inhibitors; D012235:Rhodamines; C401833:tetramethylrhodamine methyl ester; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D017228:Hepatocyte Growth Factor; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D016650:Fluorescein-5-isothiocyanate; D017239:Paclitaxel; D002945:Cisplatin; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one