Abstract 3118: ESE1/ELF3 and constitutive activation of NF-kB in human prostate cancer: prognostic relevance and rationale for context-dependent therapeutic strategies.

Abstract

Abstract Activation of inflammatory circuits occurs frequently in human cancers. Here, we show that ESE1/ELF3 exerts oncogenic functions and is an important link between inflammatory signaling and prostate cancer progression. We found that ESE1/ELF3 is overexpressed in human primary and metastatic prostate tumors, mediates key transforming phenotypes in prostate cancer cells and induces transcriptional changes in relevant oncogenic pathways. Moreover, ESE1/ELF3 contributes to IL-1beta induced and constitutive activation of NF-kB by multiple transcriptional and post-transcriptional mechanisms. ESE1/ELF3 interacts with p65/RELA and p50/NFKB1, enhances nuclear localization and transcriptional activity of the NF-kB complex, and induces transcription of p50/NFKB1by binding to the gene promoter. This positive feedback loop leading to ESE1/ELF3 upregulation and NF-kB activation is also active in human prostate tumors. Bioinformatic analyses revealed that the ESE1/ELF3 transcriptional program converged with NF-kB and IL-1beta target genes in experimental models and human tumors. Furthermore, human prostate tumors with high ESE1/ELF3 expression were enriched of ESE1/ELF3 and NF-kB target genes. Evaluation of tumor tissue microarrays by immunohistochemistry and of multiple gene expression datasets revealed that combined upregulation of ESE1/ELF3 and p65/p50 was associated with significantly reduced overall survival and increased disease recurrence. Furthermore, we speculated that the positive feedback loop between ESE1/ELF3 and NF-kB could be selectively disrupted by NF-kB inhibitors. To test this hypothesis, we used BAY-117085, a known inhibitor of NF-kB, and a second compound, EC-70124, which was recently reported to potently inhibit NF-kB. Both compounds inhibited NF-kB reporter activity in prostate cancer cells and reduced phosphorylation of IkBα. Moreover, expression of genes induced by ESE1/ELF3, cell migration and proliferation were significantly reduced by NF-kB inhibitors selectively in ESE1/ELF3 expressing cells. Collectively, this study provides a mechanistic link between inflammation and prostate cancer progression and suggests new tools for patient stratification and design of context-dependent strategies for a subset of prostate cancer patients with clinically aggressive and high risk tumors marked by ESE1/ELF3 and NF-kB activation. Citation Format: Nicole Longoni, Domenico Albino, Gianluca Civenni, Sandra Pinton, Maurizia Mello-Grand, Paola Ostano, Gioacchino D’ Ambrosio, Fausto Sessa, George N. Thalmann, Manuela Sarti, Ramon Garcia-Escudero, Francisco Morris, Giovanna Chiorino, Carlo V. Catapano, Giuseppina M. Carbone. ESE1/ELF3 and constitutive activation of NF-kB in human prostate cancer: prognostic relevance and rationale for context-dependent therapeutic strategies. [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 3118. doi:10.1158/1538-7445.AM2013-3118