Abstract 1042: Suppression of colorectal cancer cell proliferation by resveratrol involves upregulation of the non-canonical ligand Wnt9a
Authors: Ali Irshad , Fagla Bani M. , Braun Donald P. 
Published: August 2015

Our previous studies showed that the suppression of colorectal cancer (CRC) cell proliferation by resveratrol (RV) was accompanied by a disproportionate increase of the non-canonical Wnt signaling pathway (N-CAN) components relative to the canonical Wnt signaling pathway (CAN) components. Wnt signaling, which consists of CAN and N-CAN is an intricate ensemble of signaling components involved with various cellular processes. The CAN utilizes β-catenin and stimulates cell proliferation whereas the N-CAN is independent of β-catenin and is instrumental in cell differentiation.

These opposing mechanisms act in concert to maintain homeostasis in healthy tissues which is dysregulated in cancer. These observations have led us to propose a novel hypothesis that suppression of CRC proliferation may be mediated by the activation of the non-canonical Wnt pathway by nutritional supplements (NNS) such as RV. As far as we know, no known studies have determined the effects of RV on the non-canonical pathways in human CRC. The aim of this study was to determine whether suppression of CRC cell proliferation by RV involves non-canonical Wnt pathway components. CRC cells derived from surgical specimens (n = 5) 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 significantly increased N-CAN ligand Wnt A and Wnt 11(p&lt;0.01) and CAN ligand Wnt 10A (p&lt;0.05) by 18, 9 and 4-folds, respectively. RV treatment resulted in a significant decrease of CRC cell proliferation (56% inhibition; p&lt;0.01) compared to untreated cells.

This inhibition was partially reversed by IWP-2, a Wnt ligand production inhibitor. Conditioned media from CRC cells treated with RV significantly suppressed CRC cell proliferation (p&lt;0.05) compared to cells treated with conditioned media from untreated cells and that from cells treated with conditioned media from RV+IWP treated cells. Proliferation was not different in cells treated with conditioned media from untreated cells, IWP-2 or RV+IWP-2-treated cells. Wnt 9A antibody partially reversed the RV-mediated suppression of CRC cell proliferation relative to cells treated with IgG controls. To the best of our knowledge this is the first known study to show the involvement of a non-canonical Wnt pathway ligand, Wnt9A, in the suppression of CRC proliferation mediated by a NNS, resveratrol. This study suggests the presence of a novel mechanism for the suppression of CRC proliferation which entails activation of the non-canonical pathway. Given the excellent tolerance profile of NNS such as RV, the capacity of such agents to activate the non-canonical pathway to inhibit 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, Bani M. Fagla, Donald P. Braun. Suppression of colorectal cancer cell proliferation by resveratrol involves upregulation of the non-canonical ligand Wnt9a. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1042. doi:10.1158/1538-7445.AM2015-1042