268 - The Epidermal Growth Factor Receptor Inhibition Is Involved in Hexameric Procyanidins Anti-Colorectal Cancer Action

Abstract

Proanthocyanidins (PACs), oligomers of flavan 3-ols, are naturally abundant in fruits and vegetables. Dietary PACs consumption has been associated to a lower risk for colorectal cancer (CRC). We previously demonstrated that hexameric PACs (Hex) interacts with the enterocyte cell membrane in specialized rafts domain. In vitro Hex has antiproliferative and proapoptotic activity in human CRC cell lines. In order to identify the connection between these findings, this work investigated if the anti-CRC actions of Hex are related to its capacity to modulate the lipid raft-located epidermal growth factor (EGF) receptor (EGFR). Without affecting the EGFR localization at lipid rafts, Hex prevented the receptor dimerization upon EGF stimulation and inhibited the EGF-induced activation of the pro-proliferation and antiapoptotic pathways Raf/MEK/ERK and PI3K/Akt signaling cascades. EGFR immunolocalization studies and ELISA assays showed that Hex acted in part promoting EGFR internalization both in the absence and presence of EGF. Inhibition of the EGFR pathway by Hex was also evidenced by decreased phosphorylation at Tyr 1068, and increased Tyr 1045 phosphorylation. The latter provides a docking site for ubiquitin ligase c-Cbl and promotes EGFR degradation by the proteasome. Inhibition of EGFR activation, promotion of receptor internalization and upregulation of EGFR degradation pathways are evidences that Hex PACs can exert anti-CRC actions at the gastrointestinal tract via the downregulation of the EGFR pro-oncogenic signaling pathway.