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Role of the p38 MAPK pathway in cisplatin-based therapy

Oncogene volume 22, pages 3998–4006 (2003)Cite this article

Abstract

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 α/β 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.

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Acknowledgements

We appreciate the comments of Drs Sanchez Perez, Férnandez Soria, Ruiz-Hidalgo and García Bermejo. We also appreciate the assistance and advice of Drs Alvarez Vallina, Romero and Klander. This work was supported by Grants FIS (01/04075) and SAF (2001/0376). Javier Hernández Losa is supported by a FIS contract.

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  1. Unidad de Patología Molecular, Hospital Universitario Puerta de Hierro, C/San Martin de Porres 4, Madrid, 28035, Spain

    Javier Hernández Losa, Carlos Parada Cobo, Juan Guinea Viniegra, Victor Javier Sánchez-Arevalo Lobo, Santiago Ramón y Cajal & Ricardo Sánchez-Prieto

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  1. Javier Hernández Losa
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Correspondence to Ricardo Sánchez-Prieto.

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Losa, J., Cobo, C., Viniegra, J. et al. Role of the p38 MAPK pathway in cisplatin-based therapy. Oncogene 22, 3998–4006 (2003). https://doi.org/10.1038/sj.onc.1206608

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