根據(jù)在2月的《癌細(xì)胞》（Cancer Cell 2007;11:191-205.）雜志上的一項(xiàng)報(bào)告,，通過(guò)測(cè)知活性氧簇(ROS)存在和誘導(dǎo)凋亡,，p38a MAP激酶(MAPK)可抑制腫瘤起始,。
西班牙國(guó)立癌癥中心（CNIO）的Angel R. Nebreda博士及其同事研究了體外p38a對(duì)H-Ras誘導(dǎo)的成纖維細(xì)胞轉(zhuǎn)化的影響,。缺乏p38a的小鼠胚胎成纖維細(xì)胞(MEFs)比通過(guò)H-Ras轉(zhuǎn)化的野生型MEFs引起腫瘤發(fā)生顯著較快,，而p38a持續(xù)活化可抑制H-Ras誘導(dǎo)的NIH3T3成纖維細(xì)胞轉(zhuǎn)化,。缺乏p38a的H-Ras轉(zhuǎn)化細(xì)胞比H-Ras轉(zhuǎn)化的野生型細(xì)胞積聚顯著更多的ROS,，野生型H-Ras轉(zhuǎn)化細(xì)胞比H-Ras轉(zhuǎn)化的p38a缺乏細(xì)胞有10倍以上的凋亡,。
進(jìn)一步試驗(yàn)結(jié)果提示，p38a在腫瘤發(fā)生中起氧化應(yīng)激感受器的功能,，具有通過(guò)誘導(dǎo)ROS生成的癌基因下調(diào)惡性腫瘤轉(zhuǎn)化的能力,。相比之下，有高ROS水平的癌細(xì)胞系顯示p38a活化部分受損,。研究者說(shuō),，p38a通過(guò)對(duì)癌基因誘導(dǎo)的ROS反應(yīng)觸發(fā)凋亡，負(fù)向調(diào)節(jié)腫瘤起始,，p38 MAPK對(duì)人癌癥抑制的總作用可能高度依賴于腫瘤類(lèi)型和癌癥分期,。
Nebreda博士總結(jié)說(shuō)，p38a MAP激酶具有腫瘤抑制因子的作用提示,，正在被試驗(yàn)用于某些炎癥疾病治療的p38a抑制劑應(yīng)該被小心使用,。相反,，導(dǎo)致p38a活化的藥物，例如GST家族蛋白抑制劑,，可能是值得探索用于癌癥治療的一種新方法,。
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.
