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Β-Catenin-Mediated Transactivation and Cell Oncogene (2002) 21, 8414 – 8427 ª 2002 Nature Publishing Group All rights reserved 0950 – 9232/02 $25.00 www.nature.com/onc b-Catenin-mediated transactivation and cell – cell adhesion pathways are important in curcumin (diferuylmethane)-induced growth arrest and apoptosis in colon cancer cells Aruna S Jaiswal1,2, Benjamin P Marlow1,2, Nirupama Gupta1,2 and Satya Narayan*,1,2 1Department of Anatomy and Cell Biology, College of Medicine, The University of Florida, Gainesville, Florida, FL 32610, USA; 2UF Shands Cancer Center, College of Medicine, The University of Florida, Gainesville, Florida, FL 32610, USA The development of nontoxic natural agents with Introduction chemopreventive activity against colon cancer is the focus of investigation in many laboratories. Curcumin Dysregulation of the Wingless/Wnt (Wnt) signaling (feruylmethane), a natural plant product, possesses such pathway is believed to play an important role in the chemopreventive activity, but the mechanisms by which it pathogenesis of colorectal cancer (Polakis, 2000). In a prevents cancer growth are not well understood. In the simple model, Wnt signaling regulates the assembly of present study, we examined the mechanisms by which a complex consisting of Axin (and its homolog Axil curcumin treatment affects the growth of colon cancer and conductin), adenomatous polyposis coli (APC), b- cells in vitro. Results showed that curcumin treatment catenin, and glycogen synthase-3b kinase (GSK3b). causes p53- and p21-independent G2/M phase arrest and Axin binds to APC, b-catenin, and GSK3b and thereby apoptosis in HCT-116(p53+/+), HCT-116(p537/7) and promotes b-catenin phosphorylation and subsequent HCT-116(p217/7) cell lines. We further investigated the ubiquitination and degradation in the proteasome. association of the b-catenin-mediated c-Myc expression GSK3b regulates this process by phosphorylating and the cell – cell adhesion pathways in curcumin-induced components of the complex (Fearnhead et al., 2001; G2/M arrest and apoptosis in HCT-116 cells. Results Huelsken and Birchmeier, 2001). Activation of the Wnt described a caspase-3-mediated cleavage of b-catenin, signaling pathway inhibits GSK3b and stabilizes b- decreased transactivation of b-catenin/Tcf-Lef, catenin. Stabilizing mutations in b-catenin or trunca- decreased promoter DNA binding activity of the b- tion in APC also occurs both in colon cancer and catenin/Tcf-Lef complex, and decreased levels of c-Myc melanoma cells and increases the stability of b-catenin. protein. These activities were linked with decreased The stabilized pool of b-catenin associates with the Cdc2/cyclin B1 kinase activity, a function of the G2/M members of the T-cell factor (Tcf)-lymphoid enhancer phase arrest. The decreased transactivation of b-catenin factor (Lef) family of transcription factors. There are in curcumin-treated HCT-116 cells was unpreventable by four known members of the Tcf-Lef family in caspase-3 inhibitor Z-DEVD-fmk, even though the mammals. The human Tcf4 gene is specifically curcumin-induced cleavage of b-catenin was blocked in expressed in colon cancer cells (Korinek et al., 1997). Z-DEVD-fmk pretreated cells. The curcumin treatment The b-catenin/Tcf4 complex is imported into the also induced caspase-3-mediated degradation of cell – cell nucleus, where it binds to the Tcf-Lef consensus adhesion proteins b-catenin, E-cadherin and APC, which binding site, bends DNA to alter the local promoter were linked with apoptosis, and this degradation was environment, and changes the transcriptional activity prevented with the caspase-3 inhibitor. Our results of specific genes (Goss and Groden, 2000). The b- suggest that curcumin treatment impairs both Wnt catenin/Tcf-Lef complex regulates proto-oncogene and signaling and cell – cell adhesion pathways, resulting in cell cycle regulator c-myc; the G1/S-regulating cyclin G2/M phase arrest and apoptosis in HCT-116 cells. D1; the gene encoding the matrix-degrading metallo- Oncogene (2002) 21, 8414 – 8427. doi:10.1038/sj.onc. proteinase, matrysin; the AP-1 transcription factors c- 1205947 jun and fra-1; and the urokinase-type plasminogen activator receptor (Mann et al., 1999). The mechanism Keywords: curcumin; caspase-3; b-catenin; c-Myc; cell – by which these transcriptional changes contribute to cell adhesion; G2/M arrest; apoptosis early-stage colorectal carcinogenesis is still ambiguous. In addition to its function in gene regulation, b- catenin also participates in cell – cell adhesion via interactions with the members of the cadherin family *Correspondence: S Narayan, UF Shands Cancer Center, College of of proteins (Gumbiner, 2000; Polakis, 2000). The C- Medicine, Academic Research Building, Room R4-216, PO Box terminal domain of E-cadherin is shown to interact with 100232, University of Florida, Gainesville, Florida, FL 32610, USA; E-mail: [email protected]fl.edu b- and g-catenin, which associate with a-catenin and Received 9 May 2002; revised 31 July 2002; accepted 7 August form an E-cadherin complex with actin cytoskeleton. 2002 This complex maintains the stable cell – cell adhesion Curcumin-induced growth arrest and apoptosis AS Jaiswal et al 8415 (Gumbiner, 2000). APC is also a part of the cell – cell (Kuttan et al., 1987; Sharma et al., 2001). It also adhesion complex linked with E-cadherin, since it possesses anti-inflammatory properties and specifically directly binds with b-catenin, g-catenin, and actin inhibits cyclo-oxygenase-2 (COX-2) expression, which filament (Ben-Ze’ev and Geiger, 1998; Polakis, 2000). plays an important role in colon carcinogenesis (Goel In cells, in addition to its association with Wnt signaling et al., 2001). Curcumin and some other polyphenols, and cell – cell adhesion complexes, b-catenin also exists including resveratrol, tannic acid, and gallic acid, as a free pool in the cytosol (Papkoff, 1997). Thus, the induce apoptotic cell death in various cancer cell lines dynamic distribution of b-catenin in different pools may but not in normal cells (Ahmad et al., 1997; Clement et determine its role in different cellular functions. al., 1998; Inoue et al., 1994). Curcumin induces Dislodging cell – cell contacts and morphological apoptosis in melanoma cells through Fas receptor/ changes involving imbalance in the cell – cell adhesion caspase-8 (Bush et al., 2001). In prostate cancer cells, complex is one of the features of the apoptotic cells curcumin treatment down-regulates cell-survival (Pawlak and Helfman, 2001). Recent reports have mechanisms through caspase-3 and caspase-8 pathways described the proteolytic cleavage of b-catenin, g- (Mukhopadhyay et al., 2001). The p53-dependent catenin, APC, and E-cadherin during drug-induced apoptosis induced by curcumin is also reported apoptosis of cancer cells (Brancolini et al., 1998; Ling through p21 Waf1/Cip1 (hereafter p21) and GADD45 et al., 2001; Schmeiser and Grand, 1999; Steinhusen et (Jee et al., 1998). On the other hand, in human basal – al., 2001). It has been shown that disruption of the b- cell carcinoma cells, curcumin-induced apoptosis is catenin binding site in the E-cadherin cytoplasmic tail independent of p53 (Jiang et al., 1996). Curcumin also abolishes stable cell – cell adhesion, whereas a direct has a profound ability to block the NF-kB cell-survival association of E-cadherin to a-catenin does not facilitate pathway (Singh and Aggarwal, 1995) and protect skin cell – cell adhesion (Yap et al., 1997). Reports describing cells from oxidative damage in vitro (Phan et al., 2001). drug-induced survival of Rat-1 cells after b-catenin/Tcf- From these studies, it implied that curcumin treatment Lef transactivation supporting the role of decreased b- induces apoptosis and decreases cell growth in a wide catenin signaling in apoptosis (Chen et al., 2001). range of cell types. However, it is unclear whether Furthermore, it is also reported that overexpression of curcumin-induced Wnt signaling and/or cell – cell b-catenin induces apoptosis independent of the transac- adhesion pathways play a role in growth arrest and tivation activity and does not involve cell cycle regulators apoptosis of colon cancer cells. In the present study, we such as p53, Rb, cyclin D1 or E2F (Kim et al., 2000). have shown that curcumin treatment induces caspase- Thus, depending on the cell type or the stimulus received, 3-mediated b-catenin cleavage and c-Myc down- these studies indicate that both cleavage and over- regulation in the Wnt signaling pathway, resulting in expression of b-catenin can be involved in apoptosis or G2/M phase arrest. We also found that the curcumin survival of the cancer cells. Recently, b-catenin has been treatment induces apoptosis by increasing the degrada- suggested as an important target for drug design for tion of b-catenin, E-cadherin, and APC and thus preventing growth and metastasis of cancer cells through altering the cell – cell adhesion pathway. multiple pathways including Wnt signaling and cell – cell adhesion (Daniels et al., 2001). Results Among the current treatment strategies, chemopre- vention has received considerable promise as an Curcumin-induced G /M phase arrest and apoptosis of effective approach for colon cancer prevention and is 2 HCT-116 cells are p53-independent a focus of our current research efforts. Chemopreven- tion is the attempt to use dietary factors, synthetic Previous studies have demonstrated that curcumin pharmacological agents, and changes in lifestyle to induces growth arrest and apoptosis in p53-dependent intervene at the precancerous stages of carcinogenesis
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