title: P38MAPK is a major determinant of the balance between apoptosis and autophagy triggered by 5-fluorouracil: implication in resistance.
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.
authors.affiliation: Laboratorio de Oncología Molecular, Centro Regional de Investigaciones Biomédicas, CRIB/PCYTA, Universidad de Castilla-La Mancha, UCLM, Albacete, Spain.
authors.forename: M A
authors.initials: MA
authors.lastname: de la Cruz-Morcillo
authors.forename: M L L
authors.initials: ML
authors.lastname: Valero
authors.forename: J L
authors.initials: JL
authors.lastname: Callejas-Valera
authors.forename: L
authors.initials: L
authors.lastname: Arias-González
authors.forename: P
authors.initials: P
authors.lastname: Melgar-Rojas
authors.forename: E M
authors.initials: EM
authors.lastname: Galán-Moya
authors.forename: E
authors.initials: E
authors.lastname: García-Gil
authors.forename: J
authors.initials: J
authors.lastname: García-Cano
authors.forename: R
authors.initials: R
authors.lastname: Sánchez-Prieto
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D064007:Ataxia Telangiectasia Mutated Proteins; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects; D005472:Fluorouracil / Q000494:pharmacology*; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D000964:Antimetabolites, Antineoplastic; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D005472:Fluorouracil