Nitric oxide-donating aspirin inhibits colon cancer cell growth via mitogen-activated protein kinase activation
Nitric oxide-donating aspirin inhibits colon cancer cell growth via mitogen-activated protein kinase activation
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DOI：
10.1124/jpet.105.091363
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发表时间：
2006-01-01
影响因子：
3.5
通讯作者：
Rigas, B
中科院分区：
文献类型：
--
作者：
Hundley, TR;Rigas, B
一氧化氮供体阿司匹林（NO-阿司匹林），代表了一个新的概念，在更有效的非甾体抗炎药的发展，包括传统的阿司匹林轴承-ONO 2，释放NO。传统的阿司匹林预防人类结肠癌，但其毒性排除其作为一种化学预防剂的应用。NO-阿司匹林似乎更安全，在培养的癌细胞中，它的效力比阿司匹林强1000倍。为了确定NO-阿司匹林抑制细胞生长的机制，我们研究了其对HT-29人结肠癌细胞中丝裂原活化蛋白激酶（MAPK）信号的影响。NO-阿司匹林刺激细胞外信号调节激酶1/2和Akt的磷酸化只有轻微。在cJun NH 2-末端激酶（JNK）和p38 MAP激酶中观察到磷酸化的最大增加，其早在处理5分钟和1小时后就观察到，平均超过对照的10倍。JNK和p38的激活伴随着下游转录因子cJun和转录激活因子2（ATF-2）磷酸化的大幅增加。我们使用特异性MAPK抑制剂、小干扰（siRNA）基因沉默方法和显性阴性cJun来确定这些磷酸化事件与NO-阿司匹林抑制结肠癌细胞生长的能力的相关性。只有p38和JNK的双重抑制剂以及p38和cJun的组合siRNA沉默的使用消除了NO-阿司匹林阻断细胞生长的能力。我们的数据表明，NO-阿司匹林是依赖于p38和JNK MAP激酶通路的能力，以抑制结肠癌细胞的生长。
Nitric oxide-donating aspirin (NO-aspirin), representing a new concept in the development of more efficacious nonsteroidal anti-inflammatory drugs, consists of traditional aspirin bearing -ONO2, which releases NO. Conventional aspirin prevents human colon cancer, but its toxicity precludes its application as a chemopreventive agent. NO-aspirin seems safer and in cultured cancer cells it is > 1000-fold more potent than aspirin. To determine the mechanism by which NO-aspirin inhibits cell growth, we studied its effect on mitogen-activated protein kinase (MAPK) signaling in HT-29 human colon cancer cells. NO-aspirin stimulated the phosphorylation of extracellular signal-regulated kinase 1/2 and Akt only marginally. The greatest increases in phosphorylation were seen in cJun NH2-terminal kinase (JNK) and p38 MAP kinases, which were observed as early as 5 min and after 1 h of treatment, averaged more than 10-fold over control. The activation of JNK and p38 was accompanied by large increases in the phosphorylation of the downstream transcription factors cJun and activating transcription factor 2 (ATF-2). We used specific MAPK inhibitors, small interfering (siRNA) gene silencing methods, and dominant-negative cJun to determine the relevance of these phosphorylation events to the ability of NO-aspirin to inhibit colon cancer cell growth. Only the dual inhibitor of p38 and JNK and the use of combined siRNA silencing of p38 and cJun abrogated the ability of NO-aspirin to block cell growth. Our data indicate that NO-aspirin is dependent on both the p38 and the JNK MAP kinase pathways for its ability to inhibit the growth of colon cancer cells.