DAPk1 inhibits NF-κB activation through TNF-α and INF-γ-induced apoptosis

Recent studies have shown DAPk as a molecular modulator induced by the second messenger, responsible for controlling cell destiny decisions, but the detailed mechanism mediating the role of DAPk1 during cell death is still not fully understood. In this present report, we attempted to characterize the effects of TNF-alpha and INF-gamma on DAPk1 in human ovarian carcinoma cell lines, OVCAR-3. Both TNF-alpha and INF-gamma significantly induce DAPk1 levels in a time-dependent manner. At the same time, they both arrested cell cycle progression in the G(0)-G(1) and G2/M phase, down-regulated cyclin D1, CDK4 and NF-kappa B expression, while also upregulating p27 and p16 expression. Subsequently, the efficacy of the combined treatment with DAPk1 was investigated. In the presence of DAPk1, TNF-alpha or INF-gamma-induced apoptosis was additively increased, while TNF-alpha or INF-gamma-induced NF-kappa B activity was inhibited. Conversely, TNF-alpha or INF-gamma-dependent NF-kappa B activity was further enhanced by the inhibition of DAPk1 with its specific siRNA. The activity of NF-kappa B was dependent on the level of DAPk1, indicating the requirement of DAPk1 for the activation of NF-kappa B. Low levels of DAPk1 expression were frequently observed in different human patient's tissue and cancer cell lines compared to normal samples. In addition, over-expression of DAPk1 from either TNF-alpha or INF-gamma-treatment cells suppressed the anti-apoptosis protein XIAP as well as COX-2 and ICAM-1, more than control. Taken together, our data findings suggest that DAPk1 can mediate the pro-apoptotic activity of TNF-alpha and INF-gamma via the NF-kappa B signaling pathways. (c) 2012 Elsevier Inc. All rights reserved.