Affordable Access

Publisher Website

Ursolic acid and its natural derivative corosolic acid suppress the proliferation of APC-mutated colon cancer cells through promotion of β-catenin degradation

Authors
Journal
Food and Chemical Toxicology
0278-6915
Publisher
Elsevier
Volume
67
Identifiers
DOI: 10.1016/j.fct.2014.02.019
Keywords
  • Ursolic Acid
  • Corosolic Acid
  • Wnt/β-Catenin Signaling
  • Protein Degradation
  • Colon Cancer

Abstract

Abstract Ursolic acid (UA) and corosolic acid (CA), naturally occurring pentacyclic triterpene acids, exhibit antiproliferative activities against various cancer cells, but a clear chemopreventive mechanism of these triterpenoids in colon cancer cells remains to be answered. Here we used a cell-based reporter system for detection of β-catenin response transcription (CRT) to identify UA as an antagonist of the Wnt/β-catenin pathway. UA promoted the degradation of intracellular β-catenin that was accompanied by its N-terminal phosphorylation at Ser33/37/Thr41 residues, marking it for proteasomal degradation. Consistently, UA down-regulated the intracellular β-catenin level in colon cancer cells with inactivating mutations of adenomatous polyposis coli (APC). In addition, UA repressed the expression of β-catenin/T-cell factor (TCF)-dependent genes, thereby inhibiting cell proliferation in colon cancer cells. The functional group analysis revealed that the major structural requirements for UA-mediated β-catenin degradation are a carboxyl group at position 17 and a methyl group at position 19. Notably, CA (2α-hydroxyursolic acid) was also found to decrease the level of intracellular β-catenin and to suppress the growth of APC-mutated colon cancer cells. Our findings suggest that UA and CA exert their anticancer activities against colon cancer cells by promoting the N-terminal phosphorylation and subsequent proteasomal degradation of β-catenin.

There are no comments yet on this publication. Be the first to share your thoughts.