根据在2月的《癌细胞》（Cancer Cell 2007;11:191-205.）杂志上的一项报告，通过测知活性氧簇(ROS)存在和诱导凋亡，p38a MAP激酶(MAPK)可抑制肿瘤起始。
西班牙国立癌症中心（CNIO）的Angel R. Nebreda博士及其同事研究了体外p38a对H-Ras诱导的成纤维细胞转化的影响。缺乏p38a的小鼠胚胎成纤维细胞(MEFs)比通过H-Ras转化的野生型MEFs引起肿瘤发生显著较快，而p38a持续活化可抑制H-Ras诱导的NIH3T3成纤维细胞转化。缺乏p38a的H-Ras转化细胞比H-Ras转化的野生型细胞积聚显著更多的ROS，野生型H-Ras转化细胞比H-Ras转化的p38a缺乏细胞有10倍以上的凋亡。
进一步试验结果提示，p38a在肿瘤发生中起氧化应激感受器的功能，具有通过诱导ROS生成的癌基因下调恶性肿瘤转化的能力。相比之下，有高ROS水平的癌细胞系显示p38a活化部分受损。研究者说，p38a通过对癌基因诱导的ROS反应触发凋亡，负向调节肿瘤起始，p38 MAPK对人癌症抑制的总作用可能高度依赖于肿瘤类型和癌症分期。
Nebreda博士总结说，p38a MAP激酶具有肿瘤抑制因子的作用提示，正在被试验用于某些炎症疾病治疗的p38a抑制剂应该被小心使用。相反，导致p38a活化的药物，例如GST家族蛋白抑制剂，可能是值得探索用于癌症治疗的一种新方法。
Volume 11, Issue 2 , 13 February 2007, Pages 191-205
A Radical Role for p38 MAPK in Tumor Initiation
Norman J. Kennedy1, Cristina Cellurale1 and Roger J. Davis1, 2, ,
1Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
2Howard Hughes Medical Institute, Worcester, MA 01605, USA
Available online 12 February 2007.
Summary
p38α is a stress-activated protein kinase that negatively regulates malignant transformation induced by oncogenic H-Ras, although the mechanisms involved are not fully understood. Here, we show that p38α is not a general inhibitor of oncogenic signaling, but that it specifically modulates transformation induced by oncogenes that produce reactive oxygen species (ROS). This inhibitory effect is due to the ROS-induced activation of p38α early in the process of transformation, which induces apoptosis and prevents the accumulation of ROS and their carcinogenic effects. Accordingly, highly tumorigenic cancer cell lines have developed a mechanism to uncouple p38α activation from ROS production. Our results indicate that oxidative stress sensing plays a key role in the inhibition of tumor initiation by p38α.
