4.3 Article

Extracellular signal-regulated kinase 8-mediated NF-κB activation increases sensitivity of human lung cancer cells to arsenic trioxide

期刊

ONCOTARGET
卷 8, 期 30, 页码 49144-49155

出版社

IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.17100

关键词

arsenic trioxide; ERK8; I kappa Ba; MAPK15; nuclear factor-kappaB

资金

  1. National Natural Science Foundation of China [31271445, 31170785]
  2. Science and Technology Planning Project of Guangdong Province of China [2016A020215144]
  3. Guangdong Natural Science Foundation of China [S2012030006289]
  4. Department of Education of Guangdong Province [124]
  5. Department of Education, Guangdong Government under the Toptier University Development Scheme

向作者/读者索取更多资源

Extracellular signal-regulated kinase 8 (ERK8), also known as mitogen-activated protein kinase 15 (MAPK15), is the most recently identified protein kinase of the ERK family members and yet the least has been studied so far. Here, we report that ERK8 is highly expressed in several human lung cancer cell lines and is positively correlated with their sensitivities to the anti-cancer drug arsenic trioxide (As2O3). As2O3 at physiologically relevant concentrations (5-20 mu M) potently stimulates the phosphorylation of ERK8 at Thr(175) and Tyr(177) within the TEY motif in the kinase domain, leading to its activation. Interestingly, activated ERK8 interacts and directly phosphorylates IkappaBalpha (I kappa Ba) at Ser(32) and Ser(36), resulting in I kappa Ba degradation. This in turn promotes nuclear factor-kappaB (NF-kappa B) p65 nuclear translocation and chromatin-binding, as well as the subsequent induction and activation of proteins involved in apoptosis. We also show that stable short-hairpin RNA-specific knockdown of endogenous ERK8 or inhibition of NF-kappa B activity by NF-kappa B inhibitor in high ERK8 expressing lung cancer H1299 cells blunted the As2O3-induced NF-kappa B activation and cytotoxicity towards these cells, indicating the critical role of ERK8 and NF-kappa B in mediating the As2O3 effects. Taken together, our findings suggest for the first time a regulatory paradigm of NF-kappa B activation by ERK8 upon As2O3 treatment in human lung cancer cells; and implicate a potential therapeutic advantage of As2O3 that might gain more selective killing of cancer cells with high ERK8 expression.

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.3
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

暂无数据
暂无数据