Blocking effects of genistein on cell proliferation and possible mechanism in human gastric carcinoma.
ABSTRACT To study the blocking effects of genistein on cell proliferation cycle in human gastric carcinoma cells (SGC-7901) and the possible mechanism.
MTT assay was applied in the detection of the inhibitory effects of genistein on cell proliferation. Flow cytometry was used to analyze the cell cycle distribution. Immunocytochemical technique and Western blotting were performed to detect the protein expression of cyclin D1, cyclin B1 and p21(waf1/cip1).
Genistein significantly inhibited the growth and proliferation of human gastric carcinoma cells (SGC-7901). Seven days after treatment with different concentrations of genistein (2.5, 5.0, 10.0, 20.0 microg/mL), the growth inhibitory rates were 11.2%, 28.8%, 55.3%, 84.7% respectively and cell cycles were arrested at the G(2)/ M phase. Genistein decreased cyclin D1 protein expression and enhanced cyclin B1 and p21(waf/cip1) protein expression in a concentration-dependent manner.
The growth and proliferation of SGC-7901 cells can be inhibited by genistein via blocking the cell cycle, with reduced expression of cyclin D1 and enhanced expression of cyclin B1 and p21(waf/cip1) protein in the concentration range of 0-20 microg/mL.
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ABSTRACT: Increased soy consumption in Asian diets, resulting in increased serum isoflavone levels, has been associated with a decreased risk for prostate adenocarcinoma (PCa). The isoflavone genistein is believed to be the anticancer agent found in soy, and significant levels of genistein have been detected in human prostatic fluid, implicating the role of genistein in PCa prevention. Recent studies have demonstrated genistein's ability to inhibit cell growth and induce apoptosis in several cell lines; however, the molecular mechanisms of genistein's effect are not known. We have evaluated the mechanism by which genistein may inhibit PCa cell growth. Here we report that genistein inhibits PCa cell growth in culture in a dose-dependent manner, which is accompanied by a G2/M cell cycle arrest. Cell growth inhibition was observed with concomitant downregulation of cyclin B, upregulation of the p21WAF1 growth-inhibitory protein, and induction of apoptosis. Collectively, these results provide experimental evidence for a novel effect of genistein on cell cycle gene regulation, resulting in the inhibition of cell growth and ultimate demise of tumor cells.Nutrition and Cancer 02/1998; 32(3):123-31. · 2.70 Impact Factor
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ABSTRACT: As alternative medicine gains popularity in the US, a greater understanding of the proven benefits and detriments of the supplements commonly used is needed by physicians. Chemoprevention through the use of supplements or dietary means is one example. Through epidemiological studies, it is clear that there is variation in the geographic incidence of certain cancers. One such variation is in prostate cancer, for which Asian men have a decreased death rate as compared with their Western counterparts. One hypothesis for this reduction in prostate cancer deaths is due to the difference in soy consumption. The purpose of this paper is to review the effects of soy at the molecular level as well as to review the in-vivo effects. The mechanism by which soy or, more accurately, the isoflavones act is described in this review. Multiple studies attempting to clarify the effects of the isoflavones on molecular pathways will be discussed. Furthermore, recent studies demonstrating the effect of isoflavones on prostate-specific antigen, testosterone, estrogen, and hormone receptor expression in human subjects will be reviewed. After reading this review, we expect that the reader will understand the background of the isoflavones, the effect they exert at the molecular level, and their proposed benefits and limitations in human patients. However, what will be evident at the conclusion of this manuscript is the need for future studies of the effects of soy in prostate cancer patients.Current Opinion in Urology 02/2005; 15(1):17-22. · 2.20 Impact Factor
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ABSTRACT: Investigation of the basis of uncoupling of replication of the genome from mitosis in the mouse trophoblast has so far been neglected despite its significance for understanding both placental development and cell cycle control. In order to obtain clues about the molecular basis of the switch from proliferation to endoreduplication, we have investigated changes in the expression of cyclins and cyclin-dependent kinases in diploid versus giant trophoblast cells. Interestingly, while cyclin B1 transcripts were found in both diploid and giant cells, the protein was found exclusively in diploid cells. This could be explained by either inhibition of translation or by constitutive degradation of the protein. The latter was ruled out by examining blastocysts which had been cultured in the presence of the proteasome inhibitor N-acetyl-leu-leu-norleucinal followed by immunostaining for cyclin B1. In these experiments cyclin B1 protein accumulated in diploid but not in giant cells. Fusion of trophoblast giant cells with secondary oocytes, which are rich in maturation promoting factor (MPF) activity, revealed that an exogenous source of active MPF could cause chromosome condensation and nuclear envelope breakdown in endocycling cells; therefore endoreduplication via polyteny evidently requires the suppression of MPF activity. In addition, cyclin D1 transcripts were found only in giant cells and, interestingly, the beginning of its expression was evident prior to that of placental lactogen I, an early marker of trophoblast differentiation. The results suggest that supression of MPF activity, by inhibition of translation of cyclin B1, is a key mechanism for the establishment of the endocycle in the mouse trophoblast.Molecular Human Reproduction 12/1998; 4(11):1013-20. · 4.54 Impact Factor
• GASTRIC CANCER •
Blocking effects of genistein on cell proliferation and possible
mechanism in human gastric carcinoma
Hong-Bin Cui, Xiao-Lin Na, Dan-Feng Song, Ying Liu
PO Box 2345, Beijing 100023, China World J Gastroenterol 2005;11(1):69-72
Fax: +86-10-85381893 World Journal of Gastroenterology ISSN 1007-9327
E-mail: firstname.lastname@example.org www.wjgnet.com © 2005 The WJG Press and Elsevier Inc. All rights reserved.
Hong-Bin Cui, Xiao-Lin Na, Dan-Feng Song, Department of Food
Nutrition and Hygiene, Public Health College, Harbin Medical
University, Harbin 150001, Heilongjiang Province, China
Ying Liu, Department of Biotechnology, Harbin Business University,
Harbin 150076, Heilongjiang Province, China
Supported by the National Natural Science Foundation of China, No.
Correspondence to: Professor Hong-Bin Cui, 199 Dongdazhi Street,
Nangang District, Harbin 150001, Heilongjiang Province,
Telephone: +86-451-53639451 Fax: +86-451-53648617
Received: 2003-08-23 Accepted: 2003-10-27
AIM: To study the blocking effects of genistein on cell
proliferation cycle in human gastric carcinoma cells (SGC-
7901) and the possible mechanism.
METHODS: MTT assay was applied in the detection of the
inhibitory effects of genistein on cell proliferation. Flow
cytometry was used to analyze the cell cycle distribution.
Immunocytochemical technique and Western blotting were
performed to detect the protein expression of cyclin D1,
cyclin B1 and p21waf1/cip1.
RESULTS: Genistein significantly inhibited the growth and
proliferation of human gastric carcinoma cells (SGC-7901).
Seven days after treatment with different concentrations
of genistein (2.5, 5.0, 10.0, 20.0 µg/mL), the growth
inhibitory rates were 11.2%, 28.8%, 55.3%, 84.7%
respectively and cell cycles were arrested at the G(2)/ M
phase. Genistein decreased cyclin D1 protein expression
and enhanced cyclin B1 and p21waf/cip1 protein expression in
a concentration-dependent manner.
CONCLUSION: The growth and proliferation of SGC-7901
cells can be inhibited by genistein via blocking the cell cycle,
with reduced expression of cyclin D1 and enhanced expression
of cyclin B1 and p21waf/cip1 protein in the concentration range
of 0-20 µg/mL.
© 2005 The WJG Press and Elsevier Inc. All rights reserved.
Key words: Gastric carcinoma; Genistein; Cell proliferation;
Cui HB, Na XL, Song DF, Liu Y. Blocking effects of genistein
on cell proliferation and possible mechanism in human gastric
carcinoma. World J Gastroenterol 2005; 11(1): 69-72
Genistein is a natural ingredient in soybean. Recently, it has
attracted more and more attention in the field of cancer
prevention[1-3]. A number of epidemiological and laboratory
studies have shown that genistein is a potential cancer
chemopreventive agent for sex hormone-dependent cancers,
such as breast cancer and prostate cancer[4-9]. However, there
are few reports about the effect of genistein on non-sex
hormone-dependent cancers, such as gastric cancer[10-12].
Gastric cancer is common in China and supposed to be caused
by environmental factors, in which diet is an important
In this study, human gastric carcinoma cells (SGC-7901)
were used as the model in vitro to investigate the effect of
genistein on cell proliferation and its possible mechanism.
MATERIALS AND METHODS
Reagents and cell lines
Genistein (purity >98%) and trypsin were purchased from Sigma.
3H-TdR was purchased from China Atomic Energy Research
Academy. SP-9000 kit was the product of Zyme. Monoclonal
antibodies to cyclin D1, cyclin B1 and P21WAF1/CIP1 were the
products of Santa Cruz and purchased from Zhongshan Co., China.
Human gastric carcinoma cells (SGC-7901), provided by
the Cancer Research Institute of Beijing, were cultured in
RPMI1640 (Gibco) medium supplemented with 10% fetal calf
serum, penicillin (100×103 U/L) and streptomycin (100 mg/L) at
37 ¡æ in a 50 mL/L CO2 atmosphere. Genistein was dissolved in
DMSO at the concentration of 20 mg/mL and then diluted to
the required concentration with culture medium.
Assessment of cell proliferation
MTT assay was conducted to detect the cell proliferation.
SGC-7901 cells were seeded in 96- well plates, each well containing
5×103 cells. After 24 h, the culture medium was replaced by
media in which genistein concentrations were 0, 2.5, 5.0, 10.0
and 20.0 µg/mL respectively. There were four wells for each
concentration. From 1 to 7 d, one of the plates was taken out
and 20 µL fresh 3-[4,5-dimethhylthiaoly]-2,5-diphenyl-
tetrazolium bromide (MTT, 5g/L PBS) was added to each well.
After 4 h incubation, the culture media were discarded, 150 µL
of DMSO was added to each well and vibrated to dissolve
the depositor. The optical density (A value) was measured at
570 nm with a microplate reader. The inhibitory rate (IR) of
genistein on SGC-7901 cells on the 7th d was calculated as
follows: IR (%) = (1- treated group A/control group A)×100%.
Flow cytometric analysis
After an exponential growth phase, SGC-7901 cells were treated
with different concentrations of genistein (0, 5.0, 10.0 and
20.0 µg/mL) for 24 or 48 h. The cells were collected and stained
with propidium iodide (PI), then the DNA content of cells was
measured using flow cytometry to monitor the cell cycle
Cultured cells treated with genistein for 24 or 48 h were harvested
and fixed in 4% citromint solution, and then embedded in
paraffin. Four micrometer-thick sections were cut and
deparaffinized in xylene and dehydrated with graded alcohol.
Sections were treated with microwave to retrieve antigens, then
incubated overnight at 4 ¡æ with cyclin B1 and cyclin D1
antibodies (1:50 dilution) respectively. Other steps were
according to the description of SP kit. Chromogenic reaction
was developed with diaminobenzidine (DAB), and restained
with methylgreen. All sections were observed under microscope
and the number of positive cells per 1 000 cells was counted.
Western blot analysis
Cultured cells treated with genistein for 48 h were harvested
and washed with PBS. The cells were lysed in protein extract
solution. Protein concentration was determined by Coomassie
light blue methods. One hundred micrograms of cell protein
was degenerated by heat, separated on 10% polyacrylamide
gel electrophoresis and transferred to nitrocellulose filter
membrane at 30 V. The membranes were incubated with
blocking solution (containing antibodies against p21WAF1/CIP1) for
2 h at 37 ¡æ and washed twice with PBS, then incubated with
horseradish peroxidase-conjugated secondary antibodies for
1 h. Chromogenic reaction was developed with DAB and the
bands were recorded and the peak areas of protein were scanned
by the digital image instrument (ChemiImager 4000).
Data analysis was performed using Student’s t test. P<0.05
was considered statistically significant.
Inhibitory effect of genistein on SGC-7901 cell growth
MTT assay was conducted to detect the inhibitory effect of
genistein on SGC-7901 cells. As shown in Figure 1, cell proliferation
slowed down with the increase of genistein concentration and
elongation of action time in a dose- and time-dependent manner.
On d 7, the inhibitory rates of genistein on SGC-7901 cell growth
at concentrations of 2.5, 5.0, 10.0 and 20.0 µg/mL were 11.2%,
28.8%, 55.3% and 84.7%, respectively.
Figure 1 Inhibitory effect of genistein on growth of SGC-7901
cells. The cells were treated with various concentrations of
genistein for 1-7 d, the antiproloferative effect was measured
by MTT assay. Results were expressed as mean±SD from 4 wells.
Changes of cell cycle detected by flow cytometric analysis
As shown in Table 1, the cell cycle of SGC-7901 cells was
changed obviously. The number of cells in G0/G1 phase of cell
cycle was decreased gradually. The progression of cell cycle
was partly arrested at G2/M phase, but the change of S phase
Expression of cyclin B1 and cyclin D1
After SGC-7901 cells were incubated with different
concentrations of genistein for 24 and 48 h, the expression of
cyclin B1 was significantly increased while that of cyclin D1
was significantly decreased. There were significant differences
between each dosage group and control group. The results are
shown in Table 2.
Table 1 Effect of genistein on cell cycle progression of SGC-7901
24 h 48 h
S G2/ M G0/ G1 S G2/ M
19.31b 56.16b 29.41 14.43b
27.80b,d 49.85b,d 30.01 20.14b,d
32.38b,d,f 39.26b,d,f 36.88b,d,f 23.86b,d,f
64.13 29.75 6.12
bP<0.01, vs genistein 0.0 µg/ mL, dP<0.01, vs genistein 10.0 µg/mL,
fP<0.01, vs genistein 5.0 µg/ mL, aP<0.05, vs genistein 0.0 µg/ mL.
Table 2 Expression of cyclin B1 and cyclin D1 in SGC-7901 cells
treated with genistein
Genistein Positive rate (%, 24 h) Positive rate (%, 48 h)
bP<0.01, vs genistein 0.0 µg/ mL, dP<0.01, vs genistein 5.0 µg/ mL,
fP<0.01, vs genistein 10.0 µg/ mL.
Expression of p21WAF1/CIP1 protein by Western blotting
The expression of p21WAF1/CIP1 protein is shown in Figure 2 and
the peak areas of bands were analyzed with gel digit image
instrument (Figure 3). Genistein at concentrations of 2.5, 5.0,
10.0 and 20.0 µg/mL increased the expression of p21WAF1/CIP1 in
a concentration-dependent manner.
Figure 2 Expression of p21WAF1/ CIP1 protein after treated with
different genistein concentrations for 48 h.
Figure 3 Calculation of areas of p21WA F1/ CIP1 protein by
ChemiImager 4 000.
MTT chromatometry is a common method to detect cell stock
and growth. Ectogenesis of MTT can be reduced by succinic
1 2 3 4 5 6 7
A. 0 µg/mL, B. 2.5 µg/mL, C. 5.0 µg/mL, D. 10.0 µg/mL, E. 20.0 µg/mL
Marker A B C D E
70 ISSN 1007-9327 CN 14-1219/ R World J Gastroenterol January 7, 2005 Volume 11 Number 1
acid dehydrogenase existing in mitochondria of live cells and
forms indissoluble blue-purple crystal mass (formazan) and
deposits in cells. The crystal mass is dissolved by DMSO. By
detecting the A value with a microplate reader, the quantity of
live cells can be gained indirectly. The findings from our research
group suggest that genistein could significantly inhibit the
proliferation of SGC-7901 cells in a dose- and time-dependent
manner. As shown in Figure 1, the inhibitory rates of different
genistein concentrations (2.5, 5.0, 10.0 and 20.0 µg/mL) on d 7 are
11.2%, 28.8%, 55.3% and 84.7%, respectively. Genistein is a
growth inhibitor of gastric carcinoma cells, the mechanism is
unknown. However, we discovered that supplemented with
genistein, the number of SGC-7901 cells after incubation in
culture media was decreased and the cell cycle was arrested at
Cyclins are a group of proteins with cell cycle specificity. Up
to the present, cyclins A, B (B1-2), C, D (D1-3), E, F, G and H have
been found. Cyclin D1 is synthesized in pre-DNA-synthetic
gap (early G1 phase), and plays an important role in G1 to S
phase and induces cells into S phase. In general, cyclin D1 is
the key regulator of cell cycle progression and the key protein
of the signal transduction in G1 phase cell proliferation. If cyclin
D1 is over-expressed, the checkpoint of G1/S will be out of control
and lose its role in the signaling of proliferation. This further
promotes cell cycle progression and cell proliferation, and
causes carcinomatous change of cells. Thus cyclin D1 is called
the shirking protein of G1/S checkpoint. It has been proved that
cyclin D1 is overexpressed in several neoplasms, such as
esophageal carcinoma, mammary cancer, pulmonary and gastric
carcinoma. Suppressed expression of cyclin D1 in cancer
cells would help recover normal cell cycle and control
proliferation speed of tumor cells. In this study, we found that
genistein showed significant inhibition on the expression of
cyclin D1 in SGC-7901 cells, suggesting that genistein might
inhibit cell proliferation of gastric carcinoma by decreasing the
over-expression of cyclin D1.
Cyclin B1 and cyclin-dependent kinase 1 (CDK1) are two
proteins required for cells to traverse from G(2) into M. G(2)
arrest occurs in response to DNA damage caused by a variety
of agents and treatments. Cyclin B1 is synthesized in late S and
G2 phase. It binds to CDK1 and is activated to form maturation
promoting factor (MPF). Cyclin B1 is degraded in M phase. We
investigated the expression of cyclin B1 in SGC-7901 cells treated
with various concentrations of genistein for 24 and 48 h. The
results showed that the expression of cyclin B1 did not decrease
with increased concentrations of genistein as cyclin D1, instead
it increased. Some researches indicate that sustained increase
of cyclin B1 causes cell cycle blockage in cell cleavage phase.
However, other results show that when cell cycle blockage
occurs in G2/M phase, cyclin B1 is not degraded, but
accumulated in cells[16-19]. Cappelletti et al. demonstrated that
genistein could block mammary cancer cells in G2/M phase, but
the expression of cyclin B increased 2.8, 8, and 103 times
respectively in BT20, MDA-MB-231 and ZR75.1 cells. It is
stated that G2/M blockage does not always follow the decrease
of cyclin B1 expression. In this experiment, genistein blocked
SGC-7901 cell proliferation and increased the number of cells in
G2/M phase more than three times, as well as the expression of
cyclin B1. The increased cyclin B1 expression did not make
cancer cells escape the regulation of checkpoint from G2 to M
phase. Maybe it is because cyclin B1 protein accumulates during
interphase, while cell cycle progression is arrested at G2/M phase.
The molecular mechanism underlying G2/M phase blockage
requires clarification in further studies.
To find out the effect of genistein on cell proliferation cycle,
we detected the expression of CKI-p21waf1/cip1 protein by Western
blotting. Researchers previously believed that p21waf1/cip1 protein
was a regulatory factor of cell cycle in G1 phase. But now, more
and more evidence indicates the expression of p21waf/cip1 protein
relates with G2/M phase arrest[6,20-23]. While p21waf1/cip1 binds to
a variety of CDKs and cyclins, and exerts inhibitory activity on
cyclin/CDK complexes, including cyclinA-CDK1 and cyclinB1-
CDK1. Therefore p21waf/cip1 protein has an intimate relationship
with G2 and M phases of cell cycle. When SGC-7901 cells are
incubated with genistein for 48 h, the expression of p21waf1/cip1
is reduced in a dose- dependent manner. All these demonstrate
that the inhibitory effect of genistein on human gastric
carcinoma cells relates with genistein-induced expression of
p21waf/cip1 and genistein arrests tumor cells in G2/M phase.
Cell cycle regulation involves many factors and is very
complicated. The data from our studies indicate that genistein
could arrest cell cycle progression of SGC-7901 cells at G2/M
phase. The possible mechanism is that genistein promotes the
expression of p21waf1/cip1 and reduces the degradation of cyclin B1
protein in tumor cells. Therefore tumor cells are unable to pass
the checkpoint pathway of G2/M and can not proceed to mitosis.
Genistein could also inhibit the expression of cyclin D1 in tumor
cells. In a word, neoplasm is a disease of cell over-proliferation
and correlates with cell cycle regulation disorder. Genistein
inhibits tumor cell growth and proliferation by increasing the
expression of cyclin B1 and p21waf/cip1 and decreasing the
expression of cyclin D1 in SGC-7901 cells. This result suggests
that the inhibitory effect of genistein on SGC-7901 cell proliferation
relates to cell cycle.
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Edited by Wang XL, Zhang JZ and Zhu LH
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