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RETRACTED ARTICLE: P38MAPK is a major determinant of the balance between apoptosis and autophagy triggered by 5-fluorouracil: implication in resistance

Oncogene volume 31, pages 1073–1085 (2012)Cite this article

This article was retracted on 05 March 2024

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Abstract

5-Fluorouracil (5-FU), together with other drugs such as oxaliplatin, is one of the most important pharmacological agents in the treatment of colorectal cancer. Although mitogen-activated protein kinases (MAPKs) have been extensively connected with resistance to platinum compounds, no role has been established in 5-FU resistance. Here we demonstrate that p38MAPK activation is a key determinant in the cellular response to 5-FU. Thus, inhibition of p38MAPKα by SB203580 compound or by short-hairpin RNA interference-specific knockdown correlates with a decrease in the 5-FU-associated apoptosis and chemical resistance in both HaCaT and HCT116 cells. Activation of p38MAPK by 5-FU was dependent on canonical MAP2K, MAPK kinase (MKK)-3 and MKK6. In addition, ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3 related (ATR) showed a redundancy of function for the final activation of p38MAPK. Resistance associated with p38MAPK inhibition correlates with an autophagic response that was mediated by a decrease in p53-driven apoptosis, without effect onto p53-dependent autophagy. Moreover, the results with colorectal cancer-derived cell lines with different p53 status and patterns of resistance to 5-FU suggest that de novo and acquired resistance was controlled by similar mechanisms. In summary, our data demonstrate a critical role for the p38MAPK signaling pathway in the cellular response to 5-FU by controlling the balance between apoptosis and autophagy.

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Acknowledgements

This work was supported by grants from Fundacion Leticia Castillejo Castillo and Ministerio de Ciencia e Innovación (SAF2009-07329) to RSP. RSP Research Institute, and the work carried out in his laboratory, received support from the European Community through the regional development funding program (FEDER). We appreciate the comments and suggestions of Drs G Almazan, E de la Casa-Esperon, S Gutkind, D Arango, A Cuenda, A Vazquez, I Sánchez and D García-Olmo.

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  1. M L L Valero and J L Callejas-Valera: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratorio de Oncología Molecular, Centro Regional de Investigaciones Biomédicas, CRIB/PCYTA, Universidad de Castilla-La Mancha, UCLM, Albacete, Spain

    M A de la Cruz-Morcillo, M L L Valero, J L Callejas-Valera, L Arias-González, P Melgar-Rojas, E M Galán-Moya, E García-Gil, J García-Cano & R Sánchez-Prieto

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  1. M A de la Cruz-Morcillo
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Correspondence to R Sánchez-Prieto.

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de la Cruz-Morcillo, M., Valero, M., Callejas-Valera, J. et al. RETRACTED ARTICLE: P38MAPK is a major determinant of the balance between apoptosis and autophagy triggered by 5-fluorouracil: implication in resistance. Oncogene 31, 1073–1085 (2012). https://doi.org/10.1038/onc.2011.321

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