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

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 (As(2)O(3)). As(2)O(3) at physiologically relevant concentrations (5–20 μM) 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 (IκBα) at Ser(32) and Ser(36), 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 As(2)O(3)-induced NF-κB activation and cytotoxicity towards these cells, indicating the critical role of ERK8 and NF-κB in mediating the As(2)O(3) effects. Taken together, our findings suggest for the first time a regulatory paradigm of NF-κB activation by ERK8 upon As(2)O(3) treatment in human lung cancer cells; and implicate a potential therapeutic advantage of As(2)O(3) that might gain more selective killing of cancer cells with high ERK8 expression.