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From the * Laboratorio de Andrología
Celular y Molecular, Programa de Fisiología y Biofísica,
Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de
Chile, Santiago, Chile; the Departamento de
Bioquímica y Biología Molecular, Facultad de Ciencias,
Universidad de Extremadura, Badajoz, Spain; and the
Fundación Centro Nacional de
Investigaciones Cardiovasculares Carlos III, Madrid, Spain.
| Correspondence to: Dr Enrique A Castellón, Laboratory of Cell and Molecular Andrology, Physiology and Biophysics Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Independencia 1027, PO Box 70005, Santiago-7, Chile (e-mail: ecastell{at}med.uchile.cl). |
| Received for publication June 13, 2006; accepted for publication October 9, 2006. |
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Abstract |
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Key words: Cyclins/Cdk complexes, androgen sensitivity, caspases, p53, p21
Some epidemiologic studies have shown that nutritional factors may be related with carcinogenesis. Occidental fat-enriched diet correlates with high risk of prostate and other cancers, while oriental diet based on vegetables, fruit, and seeds is correlated with lower cancer risk (Adlercreutz and Mazur, 1997; Clinton and Giovannucci, 1998; Hsing et al, 2000; Romero Cagigal et al, 2003). Considering these data, a chemopreventive role for natural compounds present in natural food has been proposed. Among these substances, polyphenolic antioxidants have received increasing attention in recent years. One of such naturally occurring polyphenols is resveratrol, which is present in peanuts, grapes, and red wine (Sobolev and Cole, 1999; Fremont, 2000; Sanders et al, 2000). Also, epidemiologic studies have suggested that regular and moderate red wine consumption could have beneficial effects on human health (Maxwell et al, 1994; Goldberg et al, 1995).
Resveratrol has been shown to inhibit cancer initiation, promotion, and progression in several experimental models (Jang et al, 1997). Activation of apoptosis has been proposed as a probable mechanism for chemotherapeutic agents to eliminate cancerous cells (Naik et al, 1996; Deigner and Kinscherf, 1999). For that reason, recent studies have focused on apoptosis, as a potential process targeted by resveratrol in cancer cells. In the prostate cancer–derived cell line DU-145, a polyphenolic fraction isolated from grape seeds induces apoptosis and proliferation arrest (Agarwal et al, 2000). Also, resveratrol induces apoptosis by depolarizing mitochondrial membranes and activating caspase-9 in leukemia cells (Dorrie et al, 2001). However, in the prostate cancer cell line LNCaP the effect of resveratrol on caspase activation has not been conclusively demonstrated.
Another suggested target for resveratrol action is the control of the cell cycle. Recent data have shown that resveratrol inhibits tumor development and cellular proliferation in cancer-derived cell lines (Mgbonyebi et al, 1998; Dorrie et al, 2001; Tinhofer et al, 2001). This antiproliferative activity of resveratrol has also been shown to involve apoptosis induction in cancer cells (Ahmad et al, 2001; Dorrie et al, 2001; Tinhofer et al, 2001). In the estrogen–dependent mammary MCF-7 cells, resveratrol diminishes cell viability and induces apoptosis by modulating the expression and activity of relevant cell cycle regulators (Pozo-Guisado et al, 2002). It has been shown that resveratrol induces cell cycle arrest in prostate cell lines PC-3 and DU-145 (androgen-insensitive) but not in LNCaP (androgen-sensitive), probably by disruption of the G1/S transition (Sgambato et al, 2001). Similar results have been reported in DU-145 cells using polyphenolic extracts from grape seed (Agarwal et al, 2000). Resveratrol has structural similarity with both androgens and estrogens, and there is evidence that some of its effects might be mediated by steroid hormone receptors (Gehm et al, 1997; Bowers et al, 2000; Kampa et al, 2000). Normal prostate cells express androgen and, to a lesser extent, estrogen receptors (Latil et al, 2001; Leav et al, 2001; Royuela et al, 2001). However, in prostate cancer cells, estrogen receptors are usually overexpressed and androgen receptors, although present in sensitive stages, are normally mutated or absent in advanced metastatic disease (Veldscholte et al, 1990; Culig et al, 1993). Moreover, some effects of resveratrol might be mediated by other mechanism related with its antioxidant capacity.
In the present work, we studied the mechanisms involved in resveratrol-induced proliferation arrest and apoptosis in prostate cancer, comparing nontumorigenic, androgen-sensitive, and androgen-insensitive cancer cell lines.
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Material and Methods |
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Cell Cultures
Androgen-sensitive LNCaP and androgen-insensitive PC-3 cell lines from
human prostate cancer (American Type Culture Collection [ATCC], Manassas, Va)
were cultured in DMEM/F-12 supplemented with 10% heat-inactivated FBS, 100
units/mL penicillin G, 100 µg/mL streptomycin, and 0.25 µg/mL
amphotericin B. PZ-HPV-7 human nontumorigenic prostate epithelial cells (ATCC)
were cultured in keratinocyte-serum free medium supplemented with 0.2 ng/mL
rEGF, 30 µg/mL BPE, and 100 units/mL penicillin G, 100 µg/mL
streptomycin, and 0.25 µg/mL amphotericin B. Cultures were maintained in a
5% CO2 humidified atmosphere at 37°C. Cells were counted and
plated at the same initial density for treatments with resveratrol. At
60%–80% confluence, cells were treated with the indicated concentrations
of resveratrol dissolved in sterile DMSO. Treatments were carried out for time
periods ranging from 12 to 72 hours at trans-resveratrol
concentrations of 1 to 150 µM. Culture media were changed every day
containing fresh resveratrol. All experiments were carried out with cells at
passage 3–9.
Cell Growth Inhibition Studies
Cell growth inhibition was analyzed by the spectrophotometric measurement
of the mitochondrial dehydrogenase activity using MTT
(Mosmann, 1983). PC-3, LNCaP,
and PZ-HPV-7 cells were seeded at densities of 20, 25, and 30 x
103 cells/well, respectively, in 24-well culture plates. An
incubation time with MTT of 30 minutes was optimized for these cell lines by
determining the increase in OD (490–650 nm) with respect to time. Using
these conditions, the increase in OD (490–650 nm) was also related to
cell number by constructing linear curves with known amounts of cells
(Figure 1A through C, inserts).
After 24 hours of culture, the cells were treated with 0, 1, 10, 50, 100, or
150 µM of resveratrol for 12, 24, 48, or 72 hours. At the end of each
treatments, culture media were aspirated and cells incubated at 37°C in
Locke solution (2.3 mmol CaCl2, 1 mmol MgCl2, 5 mmol
KCl, 134 mmol NaCl, 4 mmol NaHCO3, 5 mmol glucose, 10 mmol Hepes,
pH 7.4), containing 0.35 mmol of MTT. Then, the solution was aspirated and the
formazan salts produced by active mitochondrial dehydrogenases were dissolved
in DMSO and the absorbance at 490 and 650 nm determined. The cell number was
estimated using standard curves for each cell line. Based on these
experiments, treatments with resveratrol were performed for 36 hours in LNCaP
and PC-3 cells. For direct determination of cell number, cells were plated at
the density described above and 24 hours later treated during 36 hours with
different resveratrol concentrations. Medium was aspirated and cells
tripsynized and counted. Untreated and DMSO treated cells were used as
controls. All the experiments were performed in triplicate in at least 3
cultures for each cell line.
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Flow Cytometry
Cell cycle distribution and ploidy status of cells after treatment with
resveratrol were determined by flow cytometry DNA analysis. At the end of
treatments, cells were detached from the plates by the addition of 0.25%
trypsin, washed in PBS, fixed in 70% ethanol at 4°C, and treated with 10
mg/mL RNAse for 30 minutes at 37°C. The DNA content was evaluated in a
FACScan flow cytometer (Becton Dickinson, Franklin Lakes, NJ) after staining
the cells with 50 µg/mL propidium iodide for 15 minutes in the dark at room
temperature. For cell cycle analysis, only single cells were considered.
SDS-PAGE and Western Blot
At the end of treatments with resveratrol, cells were washed with cold PBS
and lysed in ice-cold lysis buffer (50 mmol Tris-HCl pH 7.5, 2 mmol EDTA, 2
mmol EGTA, 10 mmol ß-glycerophosphate, 150 mmol NaCl, 0.5% NP40, 1 mmol
phenyl-methyl sulfonyl fluoride, 1 mmol NaF, 1 mmol DTT, 1%
ß-mercaptoethanol, and 4 µg/µL complete protease inhibitor cocktail
[Roche, Penzberg, Germany]). Cell lysates were centrifuged at 15 000 x
g for 15 minutes at 4°C, and protein concentration was determined
in the supernatants using the Coomassie Plus protein assay reagent (Pierce,
Rockford, Ill) using bovine serum albumin as standard. Fifteen micrograms of
protein were mixed with SDS sample buffer, denatured, and electrophoresed in
10% or 12% sodium dodecyl sulfate-polyacrylamide gel electrophoresis
(SDS-PAGE) gels. After electrophoresis, gels were transferred to
nitrocellulose membranes by electroblotting and blocked for 2 hours at room
temperature in TBS-T (50 mmol Tris-HCl pH 7.5, 150 mmol NaCl, 0.2% Tween-20)
containing 7% nonfat milk. Blots were sequentially incubated with the primary
and secondary antibodies, washed in TBS-T, and developed using the SuperSignal
Substrate (Pierce) and a chemiluminescence imaging screen (Bio-Rad Labs,
Hercules, Calif). The screen was scanned using a Molecular Imager FX system
from Bio-Rad Laboratories. Some membranes were developed by enhanced
chemiluminescence (ECL-Plus; Amersham Pharmacia Biotech, Piscataway, NJ) and
exposed to Kodak BioMax Light films for 1–10 minutes. In order to detect
a second protein, some blots were stripped by incubation with 100 mmol
Tris-HCl, pH 7.4, 100 mmol ß-mercaptoethanol, and 2% SDS at 60°C for
30 minutes.
Immunoprecipitation and Kinase Assay
Cultures were grown in 100-mm dishes and treated with solvent (DMSO), 1,
10, 50, 100, or 150 µM resveratrol for 36 hours. Cells were then lysed on
ice for 10 minutes with 500 µL IP buffer (50 mmol Tris–HCl pH 7.5,
150 mmol NaCl, 0.5% Nonidet P40) containing 1 mmol phenyl-methyl sulfonyl
fluoride, 1 mmol sodium orthovanadate, 1 mmol NaF, 10 mmol
ß-glycerophosphate, 1 mmol DTT, and 4 µg/µL complete protease
inhibitor cocktail. After brief mixing, lysates were centrifuged at 15 000
x g for 15 minutes at 4°C, pellets were discarded, and
protein concentration determined in the supernatants as indicated above. An
amount of 500 µg protein was used for each immunoprecipitation reaction. To
eliminate nonspecific binding, lysates were preincubated for 1 hour at 4°C
with 20 µL protein A/G Plus agarose beads. After removing the beads by
centrifugation, cell lysates were rotated overnight at 4°C with 1 µg
anti-cyclin D1 or anti-Cdk1 polyclonal antibodies. Extracts were then
incubated at 4°C for an additional 60 minutes with 30 µL protein A/G
Plus agarose beads. Beads were washed 3 times in IP buffer and twice in kinase
buffer (20 mmol Tris–HCl pH 8.0, 10 mmol MgCl2, 1 mmol EGTA, 1 mmol DTT)
and finally resuspended in a total volume of 10 µL of kinase buffer. In
vitro kinase activity was assayed at 30°C for 30 minutes in 25 µL
kinase buffer containing 10 µL protein A/G Plus agarose beads, 1 mmol NaF,
1 mmol sodium orthovanadate, 1 µg GST-Rb or 5 µg Histone H1 target
proteins, 10 µCi 32P-
-ATP (sp act 3000 Ci/mmol), and 1
mmol nonlabeled ATP. After the reaction was completed, SDS-sample buffer was
added and samples boiled for 5 minutes. The levels of phosphorylated GST-Rb or
Histone H1 were determined by SDS–PAGE electrophoresis and
autoradiography using phosphor-screens on a Molecular Imager FX System (BioRad
Laboratories).
Statistical Analysis
Data were expressed as mean ± SEM. Statistical comparison between
treatments was carried out using GraphPad Prism 4.0 (GraphPad Software, Inc,
San Diego, Calif). One-way ANOVA followed by Dunn test was applied, with
significances of P < .05, P < .01, or P <
.001.
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Results |
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Resveratrol-Induced Changes in Cell Cycle Distribution in Prostatic Cancer Cells
To analyze whether resveratrol-induced inhibition of cell growth in
prostate cancer cell lines was accompanied by alterations in cell cycle
distribution, we analyzed the percentage of cells in the different stages of
cell cycle by flow cytometry. As shown in
Figure 2, resveratrol induced
an accumulation of cells in G0/G1 both in LNCaP (from 100 µM) and PC-3
cells (from 50 µM). Similarly, the fraction of cells at G2/M also decreased
in both cell lines treated with increasing concentrations of resveratrol
(Figure 2B and C). However, a
larger number of PC-3 cells remained at G2/M phase after resveratrol
treatments compared with LNCaP cells. Further, concentrations of resveratrol
of 10 µM (PC-3) or 50 µM (LNCaP) induced a transient increase in cells
at the S phase.
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Apoptosis Induction by Resveratrol
To analyze whether the antiproliferative activity of resveratrol in LNCaP
and PC-3 cell lines was associated with increased apoptosis, the apoptotic
index was determined by flow cytometry. By measuring the fraction of cells
with sub G0/G1 DNA content, we observed that concentrations of resveratrol
below 50 µM did not induce a significant level of apoptosis in any of the
cell lines analyzed. Increasing the concentration of this molecule to 100
µM and 150 µM increased apoptosis rates to maximum values of 50% and 20%
for LNCaP and PC-3, respectively (Figure 6A
and B). The nontumorigenic prostate PZ-HPV-7 cell line had a
higher level of basal apoptosis (about 10%) that was not affected by
resveratrol at any of the concentrations used. Thus, the antiproliferative
effect of resveratrol was associated with apoptosis mainly in
androgen-dependent LNCaP cells.
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Discussion |
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Data on caspase activation by resveratrol in prostate cell lines are not conclusive, but in leukemia cells, resveratrol-induced activation of the mitochondrial pathway involving caspase-9 activity has been reported (Dorrie et al, 2001). On the other hand, a marked increase in proapoptotic bax protein and a decrease in antiapoptotic bcl-2 were induced by resveratrol in LNCaP. This result is in accordance with a recent report showing that resveratrol induced an inhibition of PI3K pathway followed by a decrease in the level of bcl-2 and an increase in proapoptotic proteins bax, bak, bid, and bad in LNCaP cells (Aziz et al, 2006). In PC-3, only a decrease in bcl-2 was noted in the presence of resveratrol without important changes in bax. However, the activation of the intrinsic apoptotic pathway is correlated with changes in the ratio of both proteins rather than with individual variations (Korsmeyer et al, 1993; Pozo-Guisado et al, 2002; Reed, 1994). Therefore, our results suggest that resveratrol induced apoptosis in LNCaP and PC-3 prostate cancer cells through alteration of the bax/bcl-2 balance and through activation of caspase-9, both processes leading to increased caspase-3 activity. In agreement, LNCaP cells, which had higher levels of caspase-9, -8, and -3 activities and elevated bax/bcl-2 ratio, also had increased apoptosis rates with respect to PC-3 cells.
Proliferation arrest is another main effect of resveratrol on cancer cells from different origins (Schneider et al, 2000; Pozo-Guisado et al, 2002; Kaneuchi et al, 2003; Larrosa et al, 2003; Kim et al, 2004; Poussier et al, 2005). Using different prostate cancer cell lines, it has been suggested that resveratrol induces disruption of the G1/S transition of the cell cycle (Sgambato et al, 2001). We have confirmed the marked effect of resveratrol on cell proliferation in nontumorigenic prostate epithelial cell line and in both prostate cancer-derived cell lines used. This inhibitory effect was dose- and time-dependent. Our data on cell cycle distribution indicate that high concentrations of resveratrol induced a marked increase in cell number in G0/G1 phase, with a corresponding decrease in the other phases in both prostate cancer cell lines. Interestingly, concentrations of this molecule between 10 and 50 µM induced a moderate, although reproducible, increase in cells at the S phase. We have reported a similar biphasic effect of resveratrol in mammary cancer cell lines (Pozo-Guisado et al, 2004). Agonist action for androgen/estrogen receptors at low concentration and antagonist activity at high concentration may be proposed as a possible explanation. The highest concentration of resveratrol resulted in almost no LNCaP cells in G2/M, while in PC-3, about 20% of cells still remained at that cell cycle phase, suggesting that G2 checkpoints might be also involved in the resveratrol effect. Studying the cyclin/Cdk complexes that regulate the 2 major cell cycle transitions, we have found that the expression of cyclins D1/E and the kinase activity of cyclin D1/Cdk4 complex, which regulates G1/S transition, were markedly reduced by resveratrol in LNCaP cells, with only a slight effect on PC-3 cells. In contrast, the expression and kinase activity of the cyclin B1/Cdk1 complex, which regulates G2/M transition, showed a significant decrease in both cell lines at concentrations of resveratrol above 50 µM. These results suggest that the G1/S and the G2/M transitions of the cell cycle might be differentially affected by resveratrol in either prostate cancer cell line. Considering that resveratrol can interact with both androgen and estrogen receptors (Gehm et al, 1997) and that LNCaP cells express androgen receptor whereas PC-3 cells have estrogen receptors alpha/beta, the differential interaction of resveratrol with these 2 type of receptors may account for the differences in the molecular mechanism showed in both cell lines. In this regard, resveratrol appears to inhibit the G1/S transition more efficiently in LNCaP than in PC-3 cells, an effect that might also help to explain the higher sensitivity to apoptosis in androgen-responsive LNCaP cells. A cell-specific mechanism of resveratrol action has been also shown in MCF-7 and MDA-MB-231 human breast cancer cells, in which apoptosis was also induced in estrogen-responsive MCF-7 but not in estrogen-unresponsive MDA-MB-231 cells (Pozo-Guisado et al, 2002; Pozo-Guisado et al, 2004). However, the presence of a very low level of beta-estrogen receptor expression in LNCaP cells may not rule out completely the influence of this receptor, but taking into account the differences in the level of expression in both cells, we consider that our suggestion is highly probable. We are currently studying this issue. Analyzing upstream modulators of cyclin/Cdk complexes, we have found that p21 and p27 were increased by resveratrol only in LNCaP cells. Consistently, the key cell cycle regulator p53 was also increased by resveratrol in this cell line. P53-dependent gene expression, as androgen receptor coactivators and activation of NFkB induced by resveratrol in LNCaP cells have also been reported (Narayanan et al, 2003). In addition, resveratrol induced, via MAPK pathway, a phosphorylation of p53 followed by an increase in p21 in a mutant p53 prostate cancer cell line (Lin et al, 2002). These data confirm that p53 and p21 (like p27 and other cell cycle regulators) are very pleiotropic proteins and are related to several molecular pathways. Considering that p21 and p27 proteins inhibit mainly G1-S cyclin/Cdk complexes, we speculate that resveratrol may be affecting the cell cycle of PC-3 cells through other regulators. Taken together, the data presented in this work indicate that resveratrol induces caspase-9-mediated apoptosis with changes in the bax/bcl-2 ratio and proliferation arrest through disruption of the G1/S and G2/M transitions. Nevertheless, the molecular mechanism of resveratrol may be different in cancer cells representative of different malignancy grades. We suggest that these differences might be explained by the distinct profile of steroid receptors present in these cell lines. Our results reinforce the use of resveratrol in the chemoprevention of prostate cancer. Although the chemopreventive action of grape juice or red wine on healthy cells is not only due to resveratrol but also to other numerous polyphenolic compounds like gallic acid, quercetin, and catechin, among others, resveratrol concentration in red wine may reach over 4 mg/L. However, data presented in this work strongly suggest that resveratrol may have therapeutic potential on malignant cells and that it could be used as a pharmacological preparation. From this perspective the potential toxicity of resveratrol in vivo is a major issue. There are very few studies on resveratrol toxicity in vivo. Recently, it has been reported that only at high doses (3 g/Kg/day), resveratrol causes moderate liver toxicity as measured by DNA array and induction of phase II metabolizing enzymes (Hebbar et al, 2005). This potentially toxic concentration is far beyond the doses used in this study. Finally, it is important to note that comparing these aspects of resveratrol effects, in the same experimental conditions, between LNCaP and PC-3 cells is very relevant considering that these cells are representative of the 2 main stages of prostate cancer, namely androgen-sensitive and androgen-insensitive tumors.
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Footnotes |
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