P38MAPK is a major determinant of the balance between apoptosis and autophagy triggered by 5-fluorouracil: implication in resistance (Retracted Article)
P38MAPK is a major determinant of the balance between apoptosis and autophagy triggered by 5-fluorouracil: implication in resistance (Retracted Article)
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DOI：
10.1038/onc.2011.321
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发表时间：
2012-03-01
期刊：
影响因子：
8
通讯作者：
Sanchez-Prieto, R.
中科院分区：
文献类型：
--
作者：
de la Cruz-Morcillo, M. A.;Valero, M. L. L.;Sanchez-Prieto, R.
5-氟尿嘧啶（5-FU）与其他药物如奥沙利铂一起，是治疗结直肠癌最重要的药理学药物之一。尽管丝裂原活化蛋白激酶（MAPK）与铂类化合物耐药广泛相关，但在5-FU耐药中尚未确定其作用。在这里，我们证明，p38 MAPK激活是一个关键的决定因素，在细胞反应5-FU。因此，SB203580化合物或短发夹RNA干扰特异性敲低对p38 MAPK α的抑制与HaCaT和HCT 116细胞中5-FU相关的凋亡和化学抗性的降低相关。5-FU对p38 MAPK的激活依赖于经典的MAPK 2K、MAPK激酶（MKK）-3和MKK 6。此外，共济失调毛细血管扩张症突变（ATM）和共济失调毛细血管扩张症和Rad3相关（ATR）显示了p38 MAPK最终激活的功能冗余。与p38MAPK抑制相关的抗性与由p53驱动的细胞凋亡减少介导的自噬反应相关，而对p53依赖性自噬没有影响。此外，具有不同p53状态和对5-FU耐药模式的结直肠癌衍生细胞系的结果表明，新生和获得性耐药由相似的机制控制。总之，我们的数据表明，p38 MAPK信号通路在细胞对5-FU的反应中通过控制细胞凋亡和自噬之间的平衡发挥关键作用。Oncogene（2012）31，1073 - 1085; doi：10.1038/onc.2011.321; 2011年8月15日在线发表
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 p38MAPK alpha 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. Oncogene (2012) 31, 1073-1085; doi:10.1038/onc.2011.321; published online 15 August 2011