Details

Autor(en) / Beteiligte

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

Titel

RETRACTED ARTICLE: P38MAPK is a major determinant of thebalance between apoptosis and autophagy triggered by 5-fluorouracil: implication inresistance

Ist Teil von

• Oncogene, 2012-03, Vol.31 (9), p.1073-1085

Ort / Verlag

New York: Nature Publishing Group

Erscheinungsjahr

2012

Quelle

Electronic Journals Library

Beschreibungen/Notizen

• 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.