Abstract A30: NF-kB activating peptides identified in genetic screen cooperate with Ras transformation by suppression of p53 linking inflammation to carcinogenesis

Chronic inflammatory conditions are frequently linked to increased risk of carcinogenesis. The transcription factor NF-kappa B acts as a central component of signaling pathways governing the inflammatory response. NF-kB is also constitutively activated in several tumors. While the tumor promoting inflammatory effects are largely attributed to activation of NFκB signaling in tumor milieu, it is unclear whether activation of inflammatory pathway alone can initiate tumorigenesis. The mechanism by which constitutive activation of NF-kB contributes to carcinogenesis remains elusive. We hypothesized that constitutive activation of NFkB by proinflammatory agents renders p53 incapable of opposing oncogene induced transformation. As pharmacological activation of NF-kB in normal cells is prone to transient effects due to feedback regulation, we performed an unbiased genetic screen for proinflammatory peptides in an NFκB-GFP reporter cell line using a lentiviral trimer peptide library spanning the coding regions of 800 extracellular ligands. We identified several pro-inflammatory peptides whose expression lead to robust activation of NFκB signaling. Suppression of p53 has been shown to be the only criteria to be met to override ras oncogene induced senescence in rodent fibroblasts, which prompted us to test the NFκB activating peptides in this model. Here, we show that indeed, these NF-kB activating peptides cooperate with oncogenic RasV12 to induce transformation in both in rat fibroblast cell line REF52 and primary mouse embryonic fibroblasts (MEFs) through r p53. Further, these Ras transformed fibroblast cells formed tumors in nude mice. Thus, pro-inflammatory genetic elements that activate NF-kappa B pathway can override Ras induced senescence to facilitate cellular transformation underscoring the importance of NFκB inhibitors in preventing initiation of tumerigenesis. Citation Format: Venkatesh Natarajan, Andrei P. Komarov, Alex Chenchik, Andrei V. Gudkov. NF-kB activating peptides identified in genetic screen cooperate with Ras transformation by suppression of p53 linking inflammation to carcinogenesis. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Synthetic Lethal Approaches to Cancer Vulnerabilities; May 17-20, 2013; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(5 Suppl):Abstract nr A30.