Abstract 1986: Tumor suppressor PDCD4 inhibits NFκB dependent transcription in human glioblastoma cells by direct interaction with p65.

Abstract

Abstract PDCD4 was first described as a protein induced by apoptotic stimuli that acts as a tumor suppressor. PDCD4 plays an important role in regulating translation and transcription. Our previous research showed that overexpression of PDCD4 leads to decreased anchorage independent growth in glioblastoma-derived cell lines as well as decreased tumor growth in a glioblastoma xenograft model. Moreover, PDCD4 positively influences tumor necrosis factor-induced activation of the transcription factor NF-κB in inflammatory cells. However, the effect of PDCD4 on NF-κB transcriptional activity in cancer cells is still unknown. NF-κB acts as an oncogenic driver in many cancer sites. We studied the effect of PDCD4 on NF-κB-dependent transcriptional activity in malignant human glioblastoma cell lines by stably overexpressing PDCD4 in GBM U251 and LN229 cells. Stable Pdcd4 expression inhibits NF-κB transcriptional activation measured by a luciferase reporter in U251 and LN229 cells. The molecular mechanism by which PDCD4 inhibits NF-κB transcriptional activation does not involve inhibited expression of NF-κB p65 or p50 proteins. PDCD4 overexpression does not inhibit pathways upstream of NF-κB including the activation of IKKalpha and IKKbeta kinases. In addition, PDCD4 does not inhibit phosphorylation or degradation of IκBα, events needed for nuclear transport of p65 and p50. Overexpression of PDCD4 does, however, inhibit translocation of p65 but not p50 to the nucleus. Pdcd4 protein interacts directly with p65 protein as shown by co-immunoprecipitation and confocal imaging. These results suggest that PDCD4 can significantly inhibit NF-κB activity in glioblastoma cells by a mechanism that involves direct protein-protein interaction rather than the expected mRNA-selective translational inhibition. These findings may provide novel opportunities for NF-κB targeted interventions to prevent or treat cancer. Citation Format: Soon-Kyung Hwang, Matthew R. Young, Nancy H. Colburn. Tumor suppressor PDCD4 inhibits NFκB dependent transcription in human glioblastoma cells by direct interaction with p65. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1986. doi:10.1158/1538-7445.AM2013-1986