Abstract 1303: Key roles for Gab1, phosphatidylinositol-3-kinase, COX-2, prostaglandin E2 and TGF-alpha in linoleic acid-induced upregulation of lung and breast cancer cell growth.

Abstract

Abstract The omega-6 polyunsaturated fatty acid, linoleic acid (LA), is prevalent in Western diets and is known to enhance the tumorigenesis of mammary cancer models; with previous work demonstrating an upregulation of phosphatidylinositol-3-kinase (PI3K) signaling may play a key role. In this study, a mechanism for LA's upregulation of cancer cell growth is defined. High levels of LA in animal diets or cell culture medium initiates a series of events beginning with increased cyclooxygenase (COX) activity, which leads to increased prostaglandin E2 (PGE2) production, that subsequently increases matrix metalloproteinase (MMP) levels and transforming growth factor alpha (TGF-α). TGF-α is a classic growth factor for the epidermal growth factor receptor 1 (EGFR), which plays a role in a large number of cancers. The Grb2-associated binding protein 1 (Gab1) is a scaffolding protein that can complex with EGFR to activate PI3K signaling. Recent studies in our laboratory reveal LA supplementation of the breast cancer cell line BT-474 and the lung adenocarcinoma cell line A549 greatly increases the association between Gab1 and EGFR, while at the same time dramatically decreasing Gab1 protein levels. These changes are concomitant with increases in activated Akt (pAkt), a downstream signaling component in the PI3K signaling pathway. Moreover, inhibitors of EGFR, PI3K and Gab1-specific siRNAs are capable of reversing LA-induced upregulation of pAkt, as well as observed increases in cell proliferation for these models. These data establish Gab1 as major target in LA-induced enhancement of tumorigenesis. Citation Format: Keith D. Kikawa, Clarissa R. Martins, Eric D. Johnson, Kristen Beck, Michael Mouradian, Ronald S. Pardini. Key roles for Gab1, phosphatidylinositol-3-kinase, COX-2, prostaglandin E2 and TGF-alpha in linoleic acid-induced upregulation of lung and breast cancer cell growth. [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 1303. doi:10.1158/1538-7445.AM2013-1303