Abstract 5356: Inactivation of Foxo3a and increased expression of Id1 by the Epstein-Barr Virus-encoded LMP1 facilitates resistance to TGF-β-mediated growth inhibition in nasopharyngeal epithelial cells

Abstract

Abstract The universal association of Nasopharyngeal carcinoma (NPC) with EBV underscores the importance of EBV infection to the development of this disease. The EBV-encoded Latent Membrane Protein-1 (LMP1) is believed to be a key factor in NPC development due to its ability to induce cellular transformation in various cell types. As a viral mimic of CD40, LMP1 functions as a constitutively active TNF receptor, altering multiple signal cascades and activating a plethora of downstream targets. LMP1 has been shown to inactivate the transcriptional activity of Foxo3a, a tumor suppressor that can inhibit the proliferation of tumor cells. LMP1 has also been found to increase expression of Id1, a transcriptional repressor that can inhibit the expression of differentiation-linked genes. Here, we report that inactivation of Foxo3a by LMP1 facilitates Id1 induction. Using a panel of LMP1 mutants, we identified the CTAR1 domain of LMP1 as being responsible for Foxo3a inactivation and Id1 upregulation. Through the use of dominant negative proteins, shRNA silencing or selective pharmacological inhibitors, we demonstrate that Foxo3a inactivation by LMP1 is mediated through the LMP1 CTAR1 domain and requires activation of the Akt and Erk-MAPK signaling pathways. Whilst engagement of the Akt, Erk-MAPK and NIK-dependent noncanonical NF-κB pathways by LMP1 are involved in Id1 upregulation, we found that LMP1 CTAR2 domain-mediated IKKβ-dependent canonical NF-κB signaling negatively regulates Id1 expression, suggesting that CTAR2 may antagonize CTAR1-mediated regulation of Id1. LMP1 has been shown to inhibit TGFβ-mediated growth inhibition by disrupting various facets of TGFβ signaling. Here we show that stable “knock-down” of Id1 in LMP1 expressing NP69 cells after stable expression of Id1-specific shRNA, reduced the growth inhibitory effect of TGFβ. The interplay between LMP1, Foxo3a and Id1 is likely to contribute to the characteristic resistance of LMP1 to TGFβ-mediated signaling and cell growth arrest. The data presented in this study may offer a novel therapeutic approach for EBV associated epithelial cancers. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5356.