Research Papers:

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

Dan-Dan Wu, Andy T.Y. Lau, Fei-Yuan Yu, Na-Li Cai, Li-Juan Dai, Myoung Ok Kim, Dong-Yan Jin and Yan-Ming Xu _

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Oncotarget. 2017; 8:49144-49155. https://doi.org/10.18632/oncotarget.17100

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Dan-Dan Wu1,*, Andy T.Y. Lau1,*, Fei-Yuan Yu1, Na-Li Cai1, Li-Juan Dai1, Myoung Ok Kim2, Dong-Yan Jin3 and Yan-Ming Xu1

1Laboratory of Cancer Biology and Epigenetics, Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, Guangdong, P.R. China

2Department of Animal Science, Kyungpook National University, Republic of Korea

3School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, P.R. China

*These authors contributed equally to this work

Correspondence to:

Yan-Ming Xu, email: [email protected]

Keywords: arsenic trioxide, ERK8, IκBα, MAPK15, nuclear factor-kappaB

Received: November 16, 2016     Accepted: April 03, 2017     Published: April 13, 2017


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 μM) potently stimulates the phosphorylation of ERK8 at Thr175 and Tyr177 within the TEY motif in the kinase domain, leading to its activation. Interestingly, activated ERK8 interacts and directly phosphorylates IkappaBalpha (IκBα) at Ser32 and Ser36, resulting in IκBα degradation. This in turn promotes nuclear factor-kappaB (NF-κB) 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-κB activity by NF-κB inhibitor in high ERK8 expressing lung cancer H1299 cells blunted the As2O3-induced NF-κB activation and cytotoxicity towards these cells, indicating the critical role of ERK8 and NF-κB in mediating the As2O3 effects. Taken together, our findings suggest for the first time a regulatory paradigm of NF-κB 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.

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