Abstract
The development of nontoxic natural agents with chemopreventive activity against colon cancer is the focus of investigation in many laboratories. Curcumin (feruylmethane), a natural plant product, possesses such chemopreventive activity, but the mechanisms by which it prevents cancer growth are not well understood. In the present study, we examined the mechanisms by which curcumin treatment affects the growth of colon cancer cells in vitro. Results showed that curcumin treatment causes p53- and p21-independent G2/M phase arrest and apoptosis in HCT-116(p53+/+), HCT-116(p53−/−) and HCT-116(p21−/−) cell lines. We further investigated the association of the β-catenin-mediated c-Myc expression and the cell–cell adhesion pathways in curcumin-induced G2/M arrest and apoptosis in HCT-116 cells. Results described a caspase-3-mediated cleavage of β-catenin, decreased transactivation of β-catenin/Tcf-Lef, decreased promoter DNA binding activity of the β-catenin/Tcf-Lef complex, and decreased levels of c-Myc protein. These activities were linked with decreased Cdc2/cyclin B1 kinase activity, a function of the G2/M phase arrest. The decreased transactivation of β-catenin in curcumin-treated HCT-116 cells was unpreventable by caspase-3 inhibitor Z-DEVD-fmk, even though the curcumin-induced cleavage of β-catenin was blocked in Z-DEVD-fmk pretreated cells. The curcumin treatment also induced caspase-3-mediated degradation of cell–cell adhesion proteins β-catenin, E-cadherin and APC, which were linked with apoptosis, and this degradation was prevented with the caspase-3 inhibitor. Our results suggest that curcumin treatment impairs both Wnt signaling and cell–cell adhesion pathways, resulting in G2/M phase arrest and apoptosis in HCT-116 cells.
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Acknowledgements
We would like to thank Dr Bert Vogelstein from the Johns Hopkins Oncology Center (Baltimore, MD, USA) for providing HCT-116(p53+/+), HCT-116(p53−/−) and HCT-116(p21−/−) cell lines and β-catenin/Tcf-Lef responsive plasmids (pTOP-FLASH, pFOP-FLASH); Dr William A Dunn from the Department of Anatomy and Cell Biology, University of Florida (Gainesville, FL, USA), for providing the N-acetyl-leucyl-leucyl-methional (ALLm), N-acetyl-leucyl-leucyl-norleucinal (ALLn), leupeptin and 3-methyladenine (3-MA), Dr Lei Zhou and Dr Lei Xiao, UF Shands Cancer Center, University of Florida (Gainesville, FL, USA) for providing reagents for TUNEL assay and anti-PARP-1 antibody, respectively. We also thank Jessica A Salinas for technical assistance and Rebecca Berg for editorial comments. The FACS analysis was performed in the FCC Laboratory of the ICBR of the University of Florida. These studies were supported in part by the grants awarded to S Narayan from the National Cancer Institute, NIH (CA77721); the 2001-Research Opportunity Fund by the University of Florida (Gainesville, FL, USA) and the 2001-Ralph E Powe Junior Faculty Enhancement Award by the Oak Ridge Associated Universities (Oak Ridge, TN, USA).
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Jaiswal, A., Marlow, B., Gupta, N. et al. β-Catenin-mediated transactivation and cell–cell adhesion pathways are important in curcumin (diferuylmethane)-induced growth arrest and apoptosis in colon cancer cells. Oncogene 21, 8414–8427 (2002). https://doi.org/10.1038/sj.onc.1205947
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DOI: https://doi.org/10.1038/sj.onc.1205947