Role of the p38 MAPK pathway in cisplatin-based therapy.
p38 MAPK has been implicated in the response to cancer therapy. To determine whether the activation of p38 MAPK could be specific to cancer therapy, we investigated the activation of p38 MAPK in response to several chemotherapeutic agents, such as cisplatin, doxorubicin and taxol in several human cell lines. Activation of p38 MAPK was measured after exposure to several chemotherapeutic agents, using specific phosphoantibodies. Only cisplatin was able to activate p38 MAPK in all the cell lines tested. Furthermore, other platinum compounds such as transplatin and platinum (IV) chloride can induce activation of p38 MAPK. The kinetics of this activation is a key event in the biological role of p38 MAPK in response to cisplatin, as we conclude from the differences observed after treatment with transplatin and cisplatin. The p38 MAPK activation is independent of the origin or genetic alterations of the cell lines and seems to be mediated through both upstream activators MKK6 and MKK3. Although the isoforms alpha/beta are mainly activated, we also demonstrated that other members of the p38 MAPK family were susceptible to activation by cisplatin when they were overexpressed in 293 T. Finally, pretreatment with specific inhibitors (SB 203580 and SKF 86002) induces a resistant phenotype in response to cisplatin. Furthermore, low activation of this SAPK pathway correlates with a resistant phenotype as demonstrated in our experimental model of head and neck cancer. Therefore, we conclude that the p38 MAPK pathway is a specific target for cisplatin-based therapy with clinical implications.
Hernández Losa
Javier
J
Unidad de Patología Molecular, Hospital Universitario Puerta de Hierro, C/San Martin de Porres 4, 28035 Madrid, Spain.
Parada Cobo
Carlos
C
Guinea Viniegra
Juan
J
Sánchez-Arevalo Lobo
Victor Javier
VJ
Ramón y Cajal
Santiago
S
Sánchez-Prieto
Ricardo
R
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D019556:COS Cells; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival; D002945:Cisplatin / Q000494:pharmacology*; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007700:Kinetics; D048371:MAP Kinase Kinase 3; D048669:MAP Kinase Kinase 6; D048291:Mitogen-Activated Protein Kinase 12; D048292:Mitogen-Activated Protein Kinase 13; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D017671:Platinum Compounds / Q000494:pharmacology; D011233:Precipitin Tests; D020033:Protein Isoforms; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction; D013844:Thiazoles / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases
D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D004791:Enzyme Inhibitors; D007093:Imidazoles; D017671:Platinum Compounds; D020033:Protein Isoforms; D011725:Pyridines; D013844:Thiazoles; C030173:platinum chloride; C034697:transplatin; C052026:6-(4-fluorophenyl)-2,3-dihydro-5-(4-pyridinyl)imidazo(2,1-b)thiazole; D048291:Mitogen-Activated Protein Kinase 12; D048292:Mitogen-Activated Protein Kinase 13; D011505:Protein-Tyrosine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048371:MAP Kinase Kinase 3; D048669:MAP Kinase Kinase 6; C482530:MAP2K3 protein, human; C482566:MAP2K6 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; C093642:SB 203580; D002945:Cisplatin