Abstract LB-425: An NF-κB pathway mediated positive feedback loop amplifies Ras activity to pathological levels in mice

Abstract

Abstract Elevated Ras activity is critical for Ras induced tumorigenesis. However, the underlying mechanisms that lead to pathological levels of Ras activity are unclear. Here, we found that stimulation of Ras signaling by typical inflammatory stimuli was transient and had no long term sequelae in wild-type mice. In contrast, these stimuli generated prolonged Ras signaling and led to chronic inflammation and precancerous lesions (PanINs) in mice expressing endogenous levels of oncogenic K-Ras. The effects of inflammatory stimuli on oncogenic Ras expressing mice were disrupted by deleting IKK2 or inhibiting Cox-2. Likewise, the expression of active IKK2 or Cox-2, or treatments with LPS generated chronic inflammation and PanINs only in mice expressing oncogenic Ras. The data support that in the presence of oncogenic Ras, inflammatory stimuli trigger an NF-κB mediated positive feedback mechanism involving Cox-2 that amplifies Ras activity to pathological levels. Because a large portion of the adult human population possesses Ras mutations in tissues including colon, pancreas, and lung, disruption of this positive feedback loop may be an important strategy for cancer prevention. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-425. doi:1538-7445.AM2012-LB-425