Antitumor Activity of Rutaecarpine in Human Colorectal Cancer Cells by Suppression of Wnt/ß-Catenin Signaling.

ABSTRACT

Alkaloids derived from natural products have been traditionally used to treat various diseases, including cancers. Rutaecarpine (1), a ß-carboline-type alkaloid obtained from Evodia rutaecarpa, has been previously reported as an anti-inflammatory agent. Nonetheless, its anticancer activity and the underlying molecular mechanisms remain to be explored. In the procurement of Wnt/ß-catenin inhibitors from natural alkaloids, 1 was found to exhibit activity against the Wnt/ß-catenin-response reporter gene. Since the abnormal activation of Wnt/ß-catenin signaling is highly involved in colon carcinogenesis, the antitumor activity and molecular mechanisms of 1 were investigated in colorectal cancer (CRC) cells. The antiproliferative activity of 1 was associated with the suppression of the Wnt/ß-catenin-mediated signaling pathway and its target gene expression in human CRC cells. 1 also induced G0/G1 cell cycle arrest and apoptotic cell death, and the antimigration and anti-invasion potential of 1 was confirmed through epithelial-mesenchymal transition biomarker inhibition by the regulation of Wnt signaling. The antitumor activity of 1 was supported in an Ls174T-implanted xenograft mouse model via Wnt target gene regulation. Overall, these findings suggest that targeting the Wnt/ß-catenin signaling pathway by 1 is a promising therapeutic option for the treatment of human CRC harboring ß-catenin mutation.