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Department of Oncology, Albert Einstein Cancer Center, Bronx, New York 10467
Abstract
Short-chain fatty acids play a critical role in colonic homeostasis because they stimulate pathways of growth arrest, differentiation, and apoptosis. These effects have been well characterized in colonic cell lines in vitro. We investigated the role of ß-catenin-Tcf signaling in these responses to butyrate and other well-characterized inducers of apoptosis of colonic epithelial cells. Unlike wild-type APC, which down-regulates Tcf activity, butyrate, as well as sulindac and trichostatin A, all inducers of G0-G1 cell cycle arrest and apoptosis in the SW620 colonic carcinoma cell line, up-regulate Tcf activity. In contrast, structural analogues of butyrate that do not induce cell cycle arrest or apoptosis and curcumin, which stimulates G2-M arrest without inducing apoptosis, do not alter Tcf activity. Similar to the cell cycle arrest and apoptotic cascade induced by butyrate, the up-regulation of Tcf activity is dependent upon the presence of a mitochondrial membrane potential, unlike the APC-induced down-regulation, which is insensitive to collapse of the mitochondrial membrane potential. Moreover, the butyrate-induced increase in Tcf activity, which is reflected in an increase in ß-catenin-Tcf complex formation, is independent of the down-regulation caused by expression of wild-type APC. Thus, butyrate and wild-type APC have different and independent effects on ß-catenin-Tcf signaling. These data are consistent with other reports that suggest that the absence of wild-type APC, associated with the up-regulation of this signaling pathway, is linked to the probability of a colonic epithelial cell entering an apoptotic cascade.
Introduction
The SCFA4 butyrate is well known to induce growth arrest, differentiation, and an apoptotic cascade in colonic carcinoma cell lines in vitro (1, 2, 3, 4, 5, 6) . This is important in regard to homeostasis of the colonic mucosa because SCFAs generated by microbial fermentation of fiber (7) are present at high concentrations in the colonic lumen (8) , where they have a physiological role in modulation of pathways related to epithelial cell maturation (9) .5 Thus, SCFAs may be active agents in the chemopreventive activity of fiber in colonic tumorigenesis (10) . However, the pathways that regulate and coordinate growth, differentiation, and apoptosis of epithelial cells in the colonic mucosa are unknown. In this study, we investigated the modulation of ß-catenin-Tcf activity in an apoptotic cascade in colonic epithelial cells stimulated by butyrate as well as other inducers.
We focused on ß-catenin signaling because this is an important pathway regulated by the APC gene. Mutations in the APC gene, coupled with loss or inactivation of the second APC allele, initiate the development of almost all human colon cancers (11) . However, there are contradictory data regarding the relationship between APC function and maturation of colonic epithelial cells. It has been reported that re-expression of a wild-type APC gene in colon carcinoma cell lines, which have only mutant endogenous APC, induces apoptosis (12) . In contrast, because activated caspases have been reported to cleave the wild-type APC protein, a step shown to be necessary in the effector phase of apoptosis (13, 14, 15) , wild-type APC may be considered a survival factor. Such a role for APC is consistent with the finding that in Drosophila, mutant APC stimulates apoptosis of retinal cells (16) .
The effects of APC on apoptosis may be mediated through its function in modulating ß-catenin-Tcf signaling. The binding of ß-catenin by APC protein, in a complex including axin and glycogen synthase kinase, targets ß-catenin for degradation, thereby generating and maintaining low levels of ß-catenin in normal cells (17, 18, 19) . However, the loss of wild-type APC abrogates this pathway, resulting in increases in ß-catenin. ß-catenin in turn forms a complex with Tcf-4, a member of the Tcf-Lef family of transcription factors, which then migrates to the nucleus where it modulates expression of target sequences (20, 21, 22, 23) . In fact, in Drosophila, the proapoptotic effects of mutant APC have been demonstrated to be due to up-regulation of the homologous pathway involving signaling through Armadillo (16) , demonstrating the intimate connection between this signaling pathway and regulation of apoptosis.
Therefore, it is unclear whether the up- or down-regulation of ß-catenin-Tcf signaling, associated with mutant or wild-type APC, respectively, stimulates apoptotic pathways in colonic epithelial cells. The data presented here on induction by butyrate and other well-characterized agents demonstrate that apoptosis is consistently linked to the up-regulation of ß-catenin-Tcf activity. Moreover, butyrate and APC are shown to act independently in modulating this signaling pathway.
Results
Up-Regulation of Tcf Activity by Inducers of Apoptosis.
We used luciferase reporter constructs containing a mouse minimal c-fos promoter linked to either copies of the wild-type Tcf binding site or a mutated version of the site to assay Tcf activity (22)
. Butyrate up-regulates c-fos expression (24)
, and the c-fos promoter alone was induced by butyrate (not shown). However, the use of the dual plasmid TOP/FOP system (Fig. 1A)
and determination of the ratio of luciferase expression linked to either the TOP (wild-type Tcf binding sites) or FOP (mutant Tcf binding sites) sequences specifically assayed the contribution of Tcf activity to expression of the luciferase reporter (22)
.
|
shows a time course of Tcf activity (TOP/FOP ratio) in response to treatment of cells with 5 mM butyrate. The effects of butyrate on differentiation, cell cycle arrest, and apoptosis of colonic carcinoma cell lines have been studied extensively, and this concentration is now commonly used (2, 3, 4, 5)
. Although the concentration of butyrate in contact with colonic epithelial cells is unknown, the lumenal concentration of butyrate in humans is 
20 mM. Thus, levels in the 5 mM range are readily achievable in vivo (8)
. Butyrate induced a 2-fold increase in Tcf activity (T/F ratio) at 8 h, which increased steadily until 24 h. This time course encompassed important events in the response of the cells to butyrate that have been established previously: by 16 h, a G0-G1 cell cycle arrest, dissipation of the mitochondrial membrane potential, and caspase-3 activation; and by 24 h, appearance of cells with fragmented DNA, an index of the final stages of apoptosis (4
, 5)
. Fig. 1C
summarizes the data of six separate experiments, each performed in triplicate, and establishes that 24-h exposure to butyrate resulted in a 3-fold increase in the mean level of expression modulated by the Tcf binding site (P < 0.001).
To determine whether the increase in Tcf activity was linked to the induction of G0-G1 arrest and an apoptotic cascade, we used structurally related compounds that do not stimulate these responses. We previously have shown that two inefficiently metabolized analogues of butyrate, isobutyric acid and heptafluorobutyric acid, do not induce cycle arrest or an apoptotic cascade in colonic carcinoma cell lines (2
, 3
, 5)
. Therefore, transfection experiments with the pTOP/FOPFLASH system were performed in triplicate, and cells were treated with either 5 mM isobutyric acid or 5 mM heptafluorobutyric acid for 24 h. As shown in Fig. 1C
, neither compound altered Tcf activity, consistent with a link between up-regulation of Tcf activity and butyrate-induced apoptosis.
We next asked whether this up-regulation of Tcf activity was observed consistently with other, structurally unrelated, inducers of apoptosis of colonic cells. These included TSA (25 , 26) , which like butyrate is an inhibitor of histone deacetylase activity (27) , and sulindac, a well-studied nonsteroidal anti-inflammatory drug that also induces apoptosis, possibly linked to its action as an inhibitor of cyclooxygenase activity (28) . It is important to note that unlike butyrate, neither compound stimulates differentiation markers in colonic epithelial cells (28) .6 To gain further insight, curcumin, a chemopreventive agent for colon carcinoma cells that induces a G2-M arrest without inducing apoptosis, was also used (29) .
A time course of the effects of each of these agents on cell cycle parameters revealed that like butyrate, TSA and sulindac induced a G0-G1 arrest, whereas an arrest in G2-M was seen with curcumin, confirming other reports (data not shown; Refs. 25
, 28 , 29
). This is summarized in Fig. 2
, which shows the results at 16 h of treatment for each inducer. Similar to butyrate, TSA and sulindac initiated an apoptotic cascade characterized by dissipation of 
m (Fig. 3A)
. However, no disruption of m was seen with curcumin, consistent with the finding that the percentage of apoptotic cells increased with TSA and sulindac, but not with curcumin (Fig. 3B)
. Each of the compounds that caused a G0-G1 arrest and an apoptotic cascade (i.e., butyrate, TSA, and sulindac) also elevated Tcf activity (Fig. 3C)
. In contrast, curcumin, which induced a G2-M arrest without apoptosis, was ineffective in altering Tcf activity.
|
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We first addressed whether butyrate stimulation of Tcf activity was abrogated by down-regulation induced by wild-type APC. Consistent with reports in other cell lines, reconstitution of wild-type APC expression in SW620 cells reduced T/F expression by 80–90% (Fig. 4A)
. When a saturating concentration of the wild-type APC expression vector was used, butyrate increased Tcf activity similarly in the absence or presence of wild-type APC expression (Fig. 4B)
. It should be noted that, in Fig. 4B
, the data for cells without and with wild-type APC expression were plotted on the left and right Y axes, respectively, which have different scales, making it clear that in this experiment APC was effective in reducing basal levels of Tcf expression (e.g., Fig. 4A
). Therefore, although APC decreased T/F expression by down-regulating ß-catenin-Tcf complex formation, it did not interfere with butyrate up-regulation of Tcf activity.
|
m. Collapse of the m eliminates not only butyrate-induced caspase-3 activation and subsequent end stages of apoptosis, but also the butyrate induction of p21WAF1/cip1 and the G0-G1 cell cycle arrest (4
, 5)
. Valinomycin, a potassium ionophore that collapses the m (4
, 5)
, abrogated the ability of butyrate to up-regulate Tcf activity and reduced the relative level of butyrate induction from 2.8 to 1.0 (Fig. 5A
; P < 0.01). In contrast, the ability of APC to down-regulate Tcf activity was not altered by valinomycin (Fig. 5B)
.
|
presents the results of a gel-shift assay to analyze ß-catenin-Tcf complex formation in control and butyrate-treated SW620 cells, using an oligomer that contains the Tcf binding site and the same methodology used for analysis of other colonic carcinoma cell lines (22
, 23)
. The first lane of each panel shows bands similar to those reported previously. These have been identified as a nonspecific band, Tcf complex, and a ß-catenin-Tcf complex (22
, 23)
. Competition for binding with an unlabeled oligomer containing the wild-type Tcf binding site but not oligomers containing the mutant Tcf binding site or an unrelated sequence confirmed that the upper two bands were specific Tcf complexes. Similarly, an anti-ß-catenin antibody supershifted the ß-catenin-Tcf complex band, whereas a nonspecific antibody did not, which confirmed that the highest molecular weight band is indeed ß-catenin-Tcf complex, as reported previously (22
, 23)
. It should also be noted that distinct, albeit much smaller shifts in the Tcf and nonspecific bands were also seen with the anti-ß-catenin antibody but not with the unrelated antibody, suggesting that each of the complexes detected may have a ß-catenin component.
|
is that complex formation was increased with extract from butyrate-treated cells compared with extract from control cells. All samples were analyzed in parallel, using equivalent amounts of protein, and exposed simultaneously to the same film; the increase with extract from butyrate-treated cells was seen in three separate experiments. Thus, the increased Tcf activity induced by butyrate (Fig. 1)
was reflected in increased ß-catenin-Tcf complex formation. Interestingly, this was not associated with increases in ß-catenin levels determined by Western blots (not shown). Discussion
SCFAs, such as butyrate, normally are present at high levels in the colonic lumen (8)
as a consequence of fermentation of dietary fiber (7)
and serve as the preferred energy source for colonic epithelial cells (7
, 8)
. In addition, SCFAs are physiological inducers of differentiation of colonic epithelial cells both in vitro and in vivo (1
, 3
, 6
, 9)
.5
In transformed colonic epithelial cell lines, treatment with the SCFA butyrate also induces growth arrest and an apoptotic cascade characterized by p53-independent up-regulation of p21WAF1/cip1, sustained G0-G1 arrest, dissipation of the m, caspase-3 activation, and finally, the terminal events in cell death (3, 4, 5)
. In this report, we have demonstrated that in SW620 cells, the butyrate-initiated pathways were also characterized by elevated Tcf activity assayed with a Tcf binding site-fos promoter-luciferase construct that was paralleled by an increase in ß-catenin-Tcf complex formation. We have also found that butyrate elevated Tcf activity in other human colonic carcinoma cell lines, including HT29, LOVO, and DLD-1 (not shown). Moreover, in SW620 cells, we have demonstrated that the stimulation and repression of Tcf activity by butyrate and APC, respectively, were brought about by different mechanisms. This is established by three observations: that butyrate modulation was sensitive to the presence of a mitochondrial membrane potential, whereas APC modulation was not; that butyrate did not increase ß-catenin levels; and that butyrate up-regulation was independent of the down-regulation induced by wild-type APC.
The up-regulation induced by butyrate appears to be linked to the induction of apoptosis because structural analogues of butyrate and the chemopreventive agent curcumin, which do not induce apoptosis, also did not stimulate Tcf activity, whereas TSA and sulindac, which both stimulate apoptosis, also up-regulated Tcf activity. This is similar to the mutant APC up-regulation of the homologous pathway in Drosophila that is responsible for retinal cell apoptosis (16) . It is unlikely, however, that up-regulation of this signaling pathway is the sole determinant of initiation and completion of an apoptotic cascade in colonic epithelial cells because the pathway is already at a high level in colonic carcinoma cells because of loss of wild-type APC. Thus, although the triggering of an apoptotic cascade is linked to up-regulation of Tcf activity, it is likely that each of the agents also modulates other factors to bring about apoptosis. These may be additional effects of the agents on targets downstream of ß-catenin-Tcf signaling or effects independent of ß-catenin-Tcf regulation. For example, c-myc is downstream in this signaling pathway, in that c-myc transcription is regulated by Tcf (30) . However, down-regulation of c-myc by butyrate (31, 32, 33, 34, 35) has been attributed to a transcriptional pause mechanism in exon 2 of the c-myc gene (34) , thus presumably overriding effects of Tcf on initiation of transcription. In addition, butyrate and TSA are inhibitors of histone deacetylase activity independent of their effects on ß-catenin-Tcf signaling (25, 26, 27) , and by altering chromatin structure, they may render loci accessible to Tcf or other transcription factors.
A final important point is that neither TSA nor sulindac stimulate differentiation markers (28) .6 Thus, the up-regulation of Tcf is more tightly linked to the stimulation of an apoptotic cascade than to differentiation, and differentiation and apoptosis may, therefore, be parallel but separable pathways. In this regard, we recently found that the Caco-2 colon carcinoma cell line, which undergoes spontaneous differentiation along the absorptive cell lineage, but not apoptosis, down-regulates Tcf activity as does wild-type APC.6 Therefore, wild-type APC may be involved in pathways of cell maturation in the colon not directly associated with apoptosis, consistent with the fact that APC is expressed in a crypt-to-lumen gradient in most cells of the colonic mucosa (36) , but only a very small percentage of cells in the mucosa undergo recognizable apoptosis as they mature (10) .5
Materials and Methods
Plasmids.
The plasmids pTOPFLASH and pFOPFLASH have been described previously (22)
. DNA was purified by the use of the Qiagen maxi-prep kit (Qiagen, Valencia, CA).
Tissue Culture and Transfections.
All experiments were performed in the SW620 colon carcinoma cell line, a cell line mutant for APC, which was grown and induced as we have reported previously (4
, 5)
. For luciferase reporter experiments, cells were grown and transfections were done in 24-well plates (Corning, Corning, NY), using Lipofectamine Reagent (Life Technologies, Inc., Gaithersburg, MD), as described previously (37)
, with 1 µg of luciferase or control vector (pCAT-Control; Promega Co., Madison, WI) and 0.33 µg of CMV-Gal per well, or were performed with Lipofectamine Plus Reagent (Life Technologies), with half the indicated amounts of DNA with 12 µl of Lipofectamine and 20 µl Plus Reagent per well. Lipofectamine Plus transfection mixes were added to 300 µl of complete medium per well. All transfections were performed overnight, and 1 ml of fresh complete medium per well was added at 21 h with or without 5 mM butyrate, 5 mM isobutyric acid, 5 mM heptafluorobutyric acid, 1.6 mM sulindac, 1.0 µM TSA, or 25 µM curcumin (all from Sigma Chemical Co., St. Louis, MO). ß-galactosidase expression from cotransfected pCMV-Gal was used to normalize transfection efficiency for analysis of the luciferase data. pCAT-Control was used as a negative control to confirm lack of luciferase activity in cells not transfected with a luciferase reporter vector and to ascertain the background level of ß-galactosidase activity in cells not transfected with CMV-Gal.
For valinomycin experiments, transfections were performed in complete medium containing 1 mM pyruvate and 5 µg/ml uridine (both from Sigma) to prevent necrotic cell death (3) . After 21 h, fresh medium containing pyruvate and uridine and, where indicated, 5 µM valinomycin (Sigma) was added, and cells were harvested 24 h later.
Expression Assays.
Luciferase and galactosidase assays were performed as described previously (37)
.
Gel-Shift Assays.
Nuclear extracts were prepared as reported (38)
, with the addition of 1 mM phenylmethylsulfonyl fluoride (Sigma) to lysis buffer containing 30% sucrose (w/v), 40 mM Tris (pH 7.5), 37 mM KCl, 12 mM MgCl2, and 0.8% Triton X-100 (Sigma). Butyrate induction was performed on cells that were 80–90% confluent, and cells were harvested after 24 h. Binding reactions were performed as reported (22)
, except that the poly(I) poly(C) concentration was adjusted from 400 to 800 ng per reaction. The double-stranded wild-type Tcf oligonucleotide (CCCTTTGATCTTACC; Promega) was labeled with the Promega 5` end-labeling kit and 
-[32P]dATP (6000Ci/mmol; NEN, Boston, MA). Competitor unlabeled oligonucleotides contained either the wild-type (above) or mutant Tcf binding site (CCCTTTGGCCTTACC) or the rat OCVDRE sequence (39)
. Anti-ß-catenin antibody was obtained from Transduction Laboratories (Lexington, KY); anti-CD4 (unrelated) antibody was from Quidel Corp (San Diego, CA). Gel shifts were performed in a 5% polyacrylamide gel in 0.25x Tris-boric acid-EDTA buffer; gels were dried, and the data were analyzed using a PhosphorImager:425 (Molecular Dynamics, Sunnyvale, CA).
Flow Cytometry.
Cell cycle parameters and the percentage of cells with a subdiploid DNA content were analyzed following uptake of propidium iodide, and the m was analyzed following uptake of the mitochondrial dye JC-1, using flow cytometry as described (4
, 5)
.
Acknowledgments
The plasmids pTOPFLASH and pFOPFLASH were a kind gift of Dr. Marc van de Wetering (University Hospital Utrecht, Utrecht, the Netherlands); the plasmid pCMV-APC was a kind gift of Dr. Bert Vogelstein (Johns Hopkins Medical School, Baltimore, MD). We thank Dave Gebhard (Albert Einstein College of Medicine, New York, NY) for assistance with flow cytometry.
Footnotes
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 Supported by Post-Doctoral Award Grant 97B004 from the American Institute for Cancer Research and Grants CA75246 and P30CA13330 from the National Cancer Institute. 
2 Current address: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520.
3 To whom requests for reprints should be addressed, at Department of Oncology, Hofheimer 509, Montefiore Medical Center, 111 E. 210th Street, Bronx, NY 10467. Phone: (718) 920-4663; Fax: (718) 882-4464; E-mail: augen{at}aecom.yu.edu
4 The abbreviations used are: SCFA, short-chain fatty acid; APC, adenomatous polyposis coli; T/F, TOP/FOP; TSA, trichostatin A; m, mitochondrial membrane potential.
5 Augenlicht, L. H., Anthony, G. M., Chruch, T. L., Edelmann, W., Kucherlapati, R., Yang, K. Y., Lipkin, M., and Heerdt, B. G. Short chain fatty acid metabolism, apoptosis, and Apc-initiated tumorigenesis in the mouse gastrointestinal tract, submitted for publication.
6 J. M. Mariadason et al., unpublished observation.
Received for publication 5/11/99. Revision received 8/ 3/99. Accepted for publication 8/ 9/99.
References
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