Triterpenoid CDDO-methyl ester inhibits the janus-activated kinase-1 (JAK1)→Signal transducer and activator of transcription-3 (STAT3) pathway by direct inhibition of JAK1 and STAT3
Triterpenoid CDDO-methyl ester inhibits the janus-activated kinase-1 (JAK1)→Signal transducer and activator of transcription-3 (STAT3) pathway by direct inhibition of JAK1 and STAT3
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DOI：
10.1158/0008-5472.can-07-3036
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发表时间：
2008-04-15
期刊：
影响因子：
11.2
通讯作者：
Kufe, Donald
中科院分区：
文献类型：
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作者：
Ahmad, Rehan;Raina, Deepak;Kufe, Donald
齐墩果烷三萜类化合物2-氰基-3，12-二氧代齐墩果烷-1，9-二烯-28-酸的C-28甲基酯（CDDO-Me）通过破坏氧化还原平衡诱导人类癌细胞凋亡，并处于临床试验中。CDDO-Me含有与硫醇亲核试剂形成可逆加合物的α，β-不饱和羰基。目前的研究表明，CDDO-Me阻断白细胞介素-6（IL-6）诱导的和组成型激活细胞中的Janus激活激酶1（JAK 1）。CDDO-Me与JAK 1在激酶结构域中的Cys（1077）处形成加合物并抑制JAK 1活性，这支持了直接机制。与这些结果一致，CDDO-Me阻断了IL-6诱导的和组成型的信号转导子和转录激活子3（STAT 3）的激活。此外，我们表明CDDO-Me（a）通过依赖于Cys（259）的烷基化的机制直接结合STAT 3，并且（B）抑制STAT 3二聚体的形成。这些发现表明，CDDO-Me通过与JAK 1和STAT 3两者形成加合物来抑制JAK 1-> STAT 3通路的激活。
The C-28 methyl ester of the oleane triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO-Me) induces apoptosis of human cancer cells by disrupting redox balance and is in clinical trials. CDDO-Me contains alpha,beta-unsaturated carbonyl groups that form reversible adducts with thiol nucleophiles. The present studies show that CDDO-Me blocks interleukin-6 (IL-6)-induced and constitutive activation of the Janus-activated kinase 1 (JAK1) in cells. In support of a direct mechanism, CDDO-Me forms adducts with JAK1 at Cys(1077) in the kinase domain and inhibits JAK1 activity. In concert with these results, CDDO-Me blocked IL-6-induced and constitutive activation of signal transducer and activator of transcription 3 (STAT3). Moreover, we show that CDDO-Me (a) binds directly to STAT3 by a mechanism dependent on the alkylation of Cys(259) and (b) inhibits the formation of STAT3 dimers. These findings indicate that CDDO-Me inhibits activation of the JAK1-->STAT3 pathway by forming adducts with both JAK1 and STAT3.