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Introduction
Gum mastic is a resinous exudation obtained from the
stem and leaves of Pistacia lentiscus trees. It has been
extensively used for centuries in Mediterranean and Middle
Eastern countries, both as a dietary supplement and herbal
remedy. Medical trials show that gum mastic may have
cytoprotective or anti-acid effects on the gastrointestinal
system, such as relief of ulcers and reducing the intensity of
gastric mucosal damage caused by anti-ulcer drugs and
aspirin with little or no side
effects[1_4]. Recent studies seem to suggest that gum mastic may exhibit antibacterial
properties[5,6]. In our previous studies, gum mastic has been shown
to inhibit the proliferation of androgen-dependent prostate
cancer LNCaP cells by inhibiting the androgen receptor (AR)
function[7]. Here it is found that gum mastic also inhibits the
growth of androgen-independent prostate cancer PC-3 cells.
Moreover, gum mastic blocks PC-3 cell cycle progression.
AR expression is absent in PC-3 cells, however, what factor
promotes its growth and what mechanisms are involved in
the inhibition of gum mastic on PC-3 cells growth? We will
try to answer these questions in this study.
The nuclear factor κB (NF-κB) proteins are a family of
transcription factors that regulate expression of genes
involved in immune and inflammatory responses, cell growth,
differentiation, and apoptosis[8].
NF-κB activity was shown to be constitutively activated in a series of
androgen-independent prostate cancer cell lines and prostate carcinoma
xenografts[9,10]. There was an inverse correlation between
AR status and constitutive activation of NF-κB. The DNA
binding activity of NF-κB in CL2 cells,
androgen-independent cells derived from androgen-sensitive LNCaP cells, was
found to be higher than in parental LNCaP
cells[11]. These data suggest that constitutive activation of
NF-κB may correlate with AR loss and may contribute to compensatory
cellular changes allowing cell survival and growth in the
absence of AR activation. To verify the crucial role of
NF-κB in the androgen-independent prostate cancer PC-3 cells, we
blocked NF-κB activity by specific inhibitor, BAY11-7082.
The results showed that PC-3 cell growth was dramatically
inhibited. It is speculated that NF-κB is a main factor in
promoting PC-3 cell proliferation.
The importance of NF-κB in the development and
progression of prostate cancer has recently become widely
recognized. Numerous studies have shown that the
suppression of constitutive NF-κB activation by certain herbal
medicines or by genetic manipulation can inhibit growth,
induce apoptosis, and enhance
chemosensitization[12_14]. Agents capable of suppressing
NF-κB activation are therefore anticipated to be potentially useful in the prevention or
treatment of prostate cancer. The present study was
undertaken to ascertain the inhibition by gum mastic on the PC-3
cells and to define the mechanisms involved in this inhibition,
taking NF-κB and the NF-κB signal as targets.
Materials and methods
Cell culture and treatments The human prostate cancer
cell line, PC-3, was obtained from the American Type Culture
Collection (Manassas, VA, USA). The cells were seeded in
35 mmol culture dishes in RPMI-1640 medium supplemented
with 10% fetal bovine serum (FBS) and 5%
CO2 at 37 °C until reaching approximately 70%_80% confluence. The cells were
treated with gum mastic at the indicated concentrations in
RPMI-1640 medium containing 5% FBS (GIBCO BRL Grand
Island, NY, USA) medium. Gum mastic (Sigma, St Louis,
MO, USA, No G0878) was dissolved in DMSO, which also
was used as a control vehicle in the cell proliferation assay
and in other analyses/assays for this study. In these assays,
every group received the same amount of DMSO.
Cell proliferation assay For the
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, the cells
were cultured in 96-well culture plates at a density of 1000
cells/well with 200 µL culture medium. After 24 h incubation,
gum mastic was added for 24 or 48 h. At the time of
evaluation of cell growth, 20 µL MTT (final concentration, 0.5
mg/mL) was added into each well. After another 4 h of incubation,
formazan crystals produced by living cultured cells were
dissolved with 100 µL DMSO to measure the absorbance at 570 nm.
Cell cycle test PC-3 cells were plated in a 50 mL culture
flask and treated with 30 µg/mL gum mastic or vehicle (0.1%
DMSO) for 24 h. Then the cells were digested by trypsin
and adjusted to the concentration of
1×106 cells/mL with PBS (137 mmol NaCl, 2.7 mmol KCl, 10 mmol
Na2HPO4, and 2 mmol
KH2PO4, pH 7.4). Based on the instructions of the CycleTEST
PLUS DNA Reagent kit (Becton Dickinson, San Jose, CA,
USA), 500 µL suspension cells were centrifuged at
800×g for 5 min at room temperature, then solution A (trypsin buffer),
solution B (trypsin inhibitor and RNase buffer), solution C
(propidium iodide stain solution) were added into the cells,
respectively, for 10 min. Finally, the cells were analyzed
using a FACScan flow cytometer (Becton Dickinson,
Mountain View, CA, USA).
Nuclear extracts The cells were grown in the same
conditions as described earlier and treated with gum mastic for
24 h. 2×109 cells were pelleted and resuspended in 1 mL cold
hypotonic buffer (10 mmol/L HEPES, pH 7.9, 1.5 mmol/L
MgCl2, 10 mmol/L KCl, 0.5 mmol/L DTT, and 0.5 mmol/L
PMSF). Following 15 min incubation on ice, the cells were
lysed by adding 50 µL of 10% NP-40 and centrifuged at 6000
×g for 5 min at 4 °C. The pellets were resuspended in 70 µL
cold hypertonic buffer (20 mmol/L HEPES, pH 7.9, 1.5
mmol/L MgCl2, 420 mmol/L NaCl, 0.2 mmol/L EDTA, 25% glycerol, 10
µg/mL aprotinin, and 0.5 mmol/L PMSF) and stirred gently at
4 °C for 30 min and centrifuged at 12
000×g for 5 min at 4 °C. The supernatant was dialyzed against the dialysis buffer (20
mmol/L HEPES, pH 7.9, 50 mmol/L KCl, 25% glycerol, 0.5
mmol/L DTT, and 0.5 mmol/L PMSF) for 2 h at 4 °C. The
protein concentration of the dialyzed nuclear extracts was
determined by the BCA method and stored at -80 °C in small
aliquots.
Western blot analysis PC-3 cells, treated with gum
mastic or 0.1% DMSO, were washed twice in cold PBS, lysed in
whole cell lysis buffer (50 mmol Tris-Cl, pH 6.8, 10% sucrose,
2% SDS, and 5% β-mercaptoethanol) and harvested on ice
for 30 min by cell scraping, and then centrifuged to get the
whole extracts. For the Western blot analysis, 40
mg nuclear extracts or total extracts were separated on 10% SDS-PAGE
and transferred to the nitrocellulose membrane. The
nitrocellulose membrane was immediately blocked with 5%
non-fat milk in PBS buffer for 1 h at room temperature. After
blocking, the membrane was incubated with specific
anti-NF-κB P65, anti-p-AKT, anti-cyclin D1, and
anti-IκBα antibodies (Santa Cruz Biotechnology Inc, Santa Cruz, CA, USA)
at 4 °C for 12 h, followed by the incubation with
peroxidase-labeled second antibody for 1 h, and immunoreactive bands
were visualized by enhanced chemiluminescence (ECL, Santa
Cruz Biotechnology Inc, USA). β-actin (BD Biosciences,
San Diego, CA, USA) was used to normalize the quantity of
the protein on the blot.
RT-PCR analysis Total RNA was isolated from the treated
cells by TRIzol reagent (Invitrogen, Carlsbad, CA, USA).
Total RNA 2 mg were used to transcribe reversibly with the
M-Mulv reverse transcriptase in the presence of random
hexamer primer. The resulting cDNA preparation was
subjected to PCR amplification using a PCR kit from TaKaRa
Biotech (Dalian, China). The primers used for the cyclin D1
were as follows: sense 5'-GAAGTTGTTGGGGCTCCTCA-GGTT-3' and antisense
5'-CTGTCGCTGGAGCCCGTG-AAAAA-3', and for the housekeeping gene
β-actin: sense 5'-GTGGGGCGCCCCAGGCACC-3' and antisense
5'-CTCCTT-AATGTCACGCACGATTT-3'. PCR conditions consisted of
initial denaturation at 94 °C for 3 min and 28 cycles of
amplification with denaturation at 94 °C for 40 s, primer-annealing
at 60 °C for 40 s, and primer extension at 72 °C for 40 s. The
final primer extension was performed at 72 °C for 10 min. The
PCR products were analyzed by electrophoresis on a 1.5%
agarose gel containing ethidium bromide and photographed
under UV light.
Transient transfection assay The luciferase reporter
plasmids containing a 5×NF-κB consensus binding motifs were
described previously[15]. Twenty-four hours before
transfection, 1×105 cells were plated in a 24-well plate. Cells
were transfected using Lipofectamine 2000 reagent
(Invi-trogen, Carlsbad, CA, USA) according to the manufacturer's
instructions. A pRL-TK plasmid was also included in the
transfections for the internal control. Following the
transfections, the cells were incubated with designated
concentrations of gum mastic for an additional 10 h in
RPMI-1640 medium containing 5% FBS, then the cell extracts were
prepared for luciferase assays using the dual Luciferase
Assay System (Promega, Madison, WI, USA). All
transfection experiments were performed in triplicate and repeated at
least 3 times.
Results
Gum mastic inhibited the proliferation of androgen-
independent prostate cancer PC-3 cells PC-3 cells, which
were hormone-refractory prostate cancer cells constitutive
for NF- κB activation, were selected for these studies. First,
we detected the effect of gum mastic on the PC-3 cells
proliferation by MTT assay. The results in Figure 1 show that
gum mastic inhibited proliferation in a
concentration-dependent and time-dependent manner. Gum mastic 40 µg/mL
inhibited the proliferation about 50% when incubated for 48 h.
Gum mastic inhibited the cell cycle progression of
PC-3 cells To further ascertain whether gum mastic affected the
cell cycle of PC-3 cells, the cell cycle distributions of gum
mastic-treated and vehicle-treated preparation were
therefore analyzed by flow cytometry. As illustrated in Figure 2,
the cells treated with gum mastic had larger populations of
cells in the G1 phase and fewer populations of cells in the S
phase, compared with the cells without gum mastic treatment.
Gum mastic inhibited NF-κB expression
NF-κB is known to be constitutively activated in PC-3 cells. When we blocked
its expression by its specific inhibitor BAY11-7082, the PC-3
cells proliferation was inhibited dramatically by MTT assay
(Figure 3A). It is speculated that NF-κB and the
NF-κB signal are critical for PC-3 cell growth. To detect whether the
inhibitory effect of gum mastic on PC-3 cells proliferation
was due to the alteration of NF-κB expression, Western
blotting was carried out to detect the change of the
NF-κB protein level. Because NF-κB functions in the nucleus, nuclear
extracts from treated and untreated PC-3 cells were used for
the analysis. The results in Figure 3B show that gum mastic
suppressed constitutive NF-κB expression in a
dose-dependent manner.
Gum mastic inhibited NF-κB binding to the κB
consensus sequence NF-κB is a transcriptional factor and binds to
the κB consensus sequence in the promoter of its target
genes to regulate their expression. To study whether the
NF-κB transcription function was affected by gum mastic,
the reporter vector containing 5×NF-κB consensus binding
motifs was used. Figure 4 shows that gum mastic inhibited
the NF-κB binding to the κB consensus sequence.
Gum mastic inhibited cyclin D1
expression Cyclin D1 is a typical NF-κB inducible gene whose promoter contains
positive κB sequence for NF-κB
binding[16]. RT-PCR was performed to determine whether the steady mRNA levels of
cyclin D1 could be affected by gum mastic. It was found that
gum mastic inhibited the cyclin D1 mRNA levels (Figure 5A).
30 µg/mL gum mastic decreased cyclin D1 mRNA levels about
50%. To further demonstrate the inhibitory effect of gum
mastic on cyclin D1 protein levels, Western blotting was
used. The results in Figure 5C show that the cyclin D1
protein levels were significantly decreased by gum mastic, which
was consistent with the effect of gum mastic on cyclin D1
mRNA levels.
Gum mastic increased IκBα expression Translocation
of NF-κB to the nucleus is normally regulated by
IκBα degradation. We examined whether the inhibition of
NF-κB activation by gum mastic was due to decreased degradation
of IκBα. Western blotting for IκBα was performed as an
index of total inhibitor protein levels. When the cells were
treated with different concentrations of gum mastic for 24 h,
significant dose-dependent increases in total IκBα protein
levels were observed (Figure 6).
Gum mastic inhibited p-AKT expression To extend
studies to the mechanisms involved in the gum mastic inhibition
of NF-κB activity, the NF-κB upstream signal factor AKT
protein levels were assayed by Western blotting. In
prostate cancer cells, when AKT has been phosphorylated, it
can activate I k kinases (IKK) and finally activate
NF-κB. So we detected the p-AKT protein levels with or without gum
mastic treatment. It was found that gum mastic inhibited the
p-AKT protein levels in PC-3 cells (Figure 7).
Discussion
Gum mastic was studied for the first time in our
laboratory and found to possess antiprostate cancer properties.
In this study, we first ascertained that gum mastic inhibited
PC-3 cell growth and promoted PC-3 cell cycle arrest. Then
we investigated the mechanisms involved in this regulatory
system. As described in the Results section, gum mastic
inhibited the NF-κB protein levels and the NF-κB signal
pathway.
NF-κB expressed ubiquitously in various cell types and
functioned as an important transcription factor governing
many aspects of cellular and organismal
physiology[8]. Mature NF-κB P65:P50 dimers are trapped in the cytoplasm
of unstimulated cells by interaction with the inhibitory
proteins termed IκBα. IKK phosphorylates IκBα proteins,
thereby targeting them to rapid ubiquitin-dependent
proteolysis that initiates the NF-κB activation. The activation of
NF-κB leads to the expression of a large number of target genes.
One of its target genes is cyclin D1, a cell cycle regulator,
whose expression contributes to cellular
proliferation[16]. One candidate kinase that may be involved in
NF-κB activation in prostate cancer cells is
PKB/AKT[17]. AKT can activate the NF-κB pathway via phosphorylation and activation of
IKK in the NF-κB pathway[18,19]. Here gum mastic inhibited
AKT expression and enhanced IκBα expression; this may
resulted in its inhibition on NF-κB activity and
NF-κB binding to κB sequence and cyclin D1 expression. The inhibitory
effects of gum mastic on NF-κB and cyclin D1 finally lead to
its induction of G1/S arrest and suppression of proliferation
in PC-3 cells.
PC-3 cell growth is androgen-independent. Androgen
and the androgen receptor play a critical role in the
development of normal prostate and prostate cancer. Endocrine
therapy for prostate cancer is aimed at reducing the level of
circulating androgens or blocking the AR function. However,
endocrine therapy is only palliative. Prostate cancer relapses
generally occur within 1_2 years and become hormone
refractory with a potentially fatal
outcome[20]. How does this happen and how do prostate cells survive after
androgen-ablation therapy?
AR can bind both to agonists, such as
dihydrotesto-sterone and to selective androgen receptor modulators which
act as antagonists or as weak agonists in a
context-dependent fashion. Resistance to anti-androgen treatment has
been postulated to reflect diverse mechanisms such as
changes of AR functions, alterations of nuclear receptor
cofactors, activation of growth factor or kinase pathways,
and decreased expression of tumor suppressors or increased
expression of anti-apoptotic
genes[21_23]. Recently Zhu et
al reported that the fundamental reason for androgen
resistance is an increased monocyte/macrophage permeated in
the prostate cancer cells and that these macrophages are a
major localized source of the inflammatory cytokines that are
linked to androgen resistance. Inflammatory cytokines
triggered the signal pathway, which repressed the genes
regulated by AR by the dismissal of the co-repressor
complex[24].
On the other hand, inflammatory cytokines can stimulate
NF-κB expression and function[25,26]. In fact,
NF-κB over-expression was detected in androgen-independent prostate
cancer cells in vitro and in
vivo[9,10]. Accumulating evidence indicated that
NF-κB is closely related to prostate cancer progression and chemotherapy
resistance[27]. In contrast to androgen-dependent LNCaP, the androgen-independent
prostate cancer cell lines, PC-3 and DU145, exhibit a high
constitutive activation of IKK and subsequent NF-κB
signaling[28]. Specific suppression of IKK expression
dramatically inhibited the proliferation of PC-3
cells[29]. Taken together, it is speculated that
NF-κB is the most important hallmark for the change from androgen-dependent to
androgen-independent, and that NF-κB is necessary for the
proliferation of androgen-independent prostate cancer cells.
Therefore, NF-κB can be taken as a potential target for
androgen-independent prostate cancer therapy.
Gum mastic inhibited NF-κB activity and the
NF-κB signal pathway and has potential properties for treating
prostate cancer. The main ingredients of gum mastic are
mono-terpenes, including α-pinene (40%) and β-myrcene (9%), by
gas chromatography mass spectrometry
analysis[30]. Many monoterpenes, including
α-pinene, may exhibit anticancer activities. We speculated that
α-pinene is a main active ingredient in gum mastic, and further study will extract the
active component from gum mastic and investigate its value
to treat prostate cancer in vitro and in
vivo. It was observed that boswellic acids extracted from other gum resins
inhibited proliferation and induced apoptosis in PC-3
cells[29]. A hexane extract from gum mastic induced apoptosis in human
colon cancer HCT116 cells[31]. Many agents inhibiting
NF-κB activity also induced
apoptosis[32,33]; however, we did not find the apoptosis in PC-3 cells treated with gum mastic
by the flow cytometer assay. Gum mastic has little effect on
the mRNA levels of bcl-xl, another NF-κB target gene which
inhibits apoptosis (data not shown). In addition to the
NF-κB pathway, further study will be required to investigate the
cytotoxic mechanisms of gum mastic against prostate cancer.
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