Abstract A84: ω3 rich diet protects against Kras-induced metaplasia via repression of NF-κB

Abstract

Expression of mutant Kras is observed and often implicated in both pancreatitis and pancreatic cancer. Yet, the means by which inflammation occurs is relatively unexplored, although a previous report supports that induction of inflammation in the presence of oncogenic Kras initiates an NF-κB–mediated positive feedback loop that incorporates Cox-2 and production of PGE2 which further amplify mutant Kras. The involvement of PGE2 is interesting, as recent data suggests diets rich in ω6 fatty acids promote Kras induced pancreatic inflammation and neoplastic lesions. However, the precise mechanism and role of epigenetic events derived from diets rich in fatty acids have yet to be completely resolved. In this work, we demonstrate that a key step in this process is the induction and accumulation of NF-κB in pancreatic epithelia, a factor sufficient to promote chronic inflammation and progression to pancreatic adenocarcinoma. In HPDE cells, inhibition of NF-κB shows promise, as treatment with the IKK inhibitor Bay11-7085 noticeably reduced levels of the pro-proliferative factor pAkt. In EL-Kras mice fed a diet rich in ω6 fatty acids, NF-kB is upregulated in the pancreas, predominantly in metaplastic lesions. Conversely, these transgenic mice fed an ω3 fatty acid diet show little, if any, NF-kB expression, which is similar to the response in mice fed an intermediate, isocaloric high fat diet. pAkt is known to act upstream of NF-κB, implicating that NF-κB may be involved in a positive feedback loop with a variety of Kras effectors culminating in pancreatitis and eventually pancreatic neoplasia/adenocarcinoma. It has also been demonstrated that the ω6 Cox2-metabolite PGE2 is mediating this response, though in cultured human pancreatic epithelia, Cox-2 inhibition showed no significant change on levels of NF-κB. Yet, Cox2 inhibition in the stroma may be synergistic with epithelial inhibition of NF-κB, offering protection against the progression from inflammation to cancer. This data provides support to multiple targets of chemoprevention and therapy, including Ras and IKK/NF-κB, for pancreatic neoplasia and cancer. Citation Format: Daniel R. Principe, Windel Emman T. Mascarinas, Chintan Chheda, Kevin Adrian, Riley Mangan, Lindsay C. Boven, Paul J. Grippo. ω3 rich diet protects against Kras-induced metaplasia via repression of NF-κB. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr A84.