Role of the p38 MAPK pathway in cisplatin-based therapy

• Published in: Oncogene Vol. 22; no. 26; pp. 3998 - 4006
• Main Authors: HERNANDEZ LOSA, Javier, PARADA COBO, Carlos, GUINEA VINIEGRA, Juan, SANCHEZ-AREVALO LOBO, Victor Javier, RAMON Y. CAJAL, Santiago, SANCHEZ-PRIETO, Ricardo
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 26.06.2003; Nature Publishing Group
• Subjects: Animals; Antineoplastic Agents - pharmacology; Biological and medical sciences; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; Cancer therapies; Cell activation; Cell cycle; Cell Line; Cell Survival; Chemotherapy; Cisplatin; Cisplatin - pharmacology; COS Cells; Cross-Linking Reagents - pharmacology; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Doxorubicin; Drug Resistance, Neoplasm; Enzyme Activation; Enzyme Inhibitors - pharmacology; Free radicals; Fundamental and applied biological sciences. Psychology; Head & neck cancer; HeLa Cells; Humans; Imidazoles - pharmacology; Isoforms; Kinases; Kinetics; MAP kinase; MAP Kinase Kinase 3; MAP Kinase Kinase 6; Mitogen-Activated Protein Kinase 12; Mitogen-Activated Protein Kinase 13; Mitogen-Activated Protein Kinase Kinases - metabolism; Mitogen-Activated Protein Kinases - metabolism; Molecular and cellular biology; Ovaries; p38 Mitogen-Activated Protein Kinases; Paclitaxel; Phenotype; Phenotypes; Phosphorylation; Plasmids - metabolism; Platinum compounds; Platinum Compounds - pharmacology; Precipitin Tests; Protein Isoforms; Protein-Tyrosine Kinases - metabolism; Pyridines - pharmacology; Radiation therapy; Signal Transduction; Thiazoles - pharmacology; Transfection; Tumor Cells, Cultured; Tumors; Genetics; p38 MAPK δ/SAPK4; p38 MAPK γ/ERK6; cisplatin; phosphorylation resistance; p38 MAPK
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1206608

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.