Abstract 3441: Suppression of colorectal cancer cell proliferation is associated with modulation of Wnt pathway signaling components by Resveratrol

Abstract

Abstract Our previous studies showed that modulation of cell cycle-regulating genes by Resveratrol (RV) is directly correlated with suppression of colorectal cancer (CRC) cell proliferation. The Wnt pathway, which consists of the canonical pathway (CAN) and non-canonical pathways (N-CAN) is an intricate ensemble of signaling components involved with cellular processes including proliferation and differentiaion. Some cell cycle regulating genes are downstream targets of the Wnt pathway. The CAN utilizes β-catenin whereas the N-CAN pathways are activated independent of β-catenin. The CAN and the N-CAN are antagonistic and modulate each other's activities. Few studies have been conducted to determine the effect of naturopathic and nutritional supplements (NNS) such as RV on the Wnt pathway in human cancers. The aim of this study was to determine whether suppression of CRC cell proliferation by RV is related to modulation of Wnt pathway components. CRC cells derived from surgical specimens (n=3) were treated with RV (5ug/ml) for 72h. Cell proliferation was determined using MTS assay and gene expression was performed using commercially available quantitative RT-PCR Wnt pathway gene expression arrays. RV treatment resulted in a significant decrease of CRC cell proliferation (52% inhibition; p<0.005) compared to untreated cells. The suppression of CRC cell proliferation by RV was correlated with modulation of both CAN and N-CAN components. The CAN components modulated significantly (p<0.05 or greater) by RV included ligand 10A (3.6 fold increase), the receptor frizzled 7 and the transcription factor TCF7L1 (2.2 and 2.6 fold decrease respectively) compared to untreated cells. The N-CAN components modulated significantly by RV were ligands 7A and 11 (2.9 and 2.5 fold increase respectively), and dishevelled-binding CAN antagonist NKD1 (2.5 fold increase) relative to untreated CRC cells. This study demonstrates that RV modulates expression of multiple components of the CAN and N-CAN pathways in CRC cells. The collective effect appears to favor N-CAN activation leading to retardation of the CAN pathway. Thus, upregulation of CAN ligand 10A is expected to be countered by the observed increase in N-CAN Wnt ligands 7A and 11, as well as CAN antagonist NKD1. This observation is consistent with our previous demonstration of the effects of RV on regulation of cell cycle gene expression in CRC leading to inhibition of cellular proliferation. Given the excellent tolerance profile of NNS such as RV, the capacity of such agents to modulate the Wnt pathway and particularly the N-CAN in favor of inhibition of tumor proliferation, offers the opportunity to investigate the effects of chronic administration of these agents on tumor growth and progression in patients. Citation Format: Irshad Ali, Adriana Rosales, Donald P. Braun. Suppression of colorectal cancer cell proliferation is associated with modulation of Wnt pathway signaling components by Resveratrol. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3441. doi:10.1158/1538-7445.AM2014-3441