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Human Genetics Program [Y. M., J. R. T.] and Ovarian Cancer Program [M. S., S. J. W., T. C. H.], Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, and Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania 19104 [S. W. J.]
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ABSTRACT |
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Introduction |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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PI3K and downstream AKT/protein kinase B family members have been implicated in disparate cell responses, including the protection of cells from apoptosis, the promotion of cell proliferation, and diverse metabolic responses (10) . In fibroblasts, activated AKT is sufficient to protect cells from apoptosis induced by serum withdrawal (11) . It has also been demonstrated that inactivation of PI3K activity markedly inhibits proliferation of small cell lung cancer cells by stimulating apoptosis and promoting cell cycle delay in G1 (12) . Furthermore, PI3K/AKT-dependent signaling stimulates the induction of cyclin D1 expression by serum and regulates its repression by herbimycin A, a drug that binds to heat shock protein 90, at the level of mRNA translation (13) . Thus, the PI3K/AKT signaling pathway seems to be involved in cell cycle regulation via ectopic stimulation factors. Of interest, it has been reported that the MEK1 inhibitor PD98059 partially inhibits PMA-induced p21 expression, whereas the PI3K inhibitor LY294002 had no such effect in the breast cancer cell line MCF-7 (14) . Here, we demonstrate a direct link between the PI3K/AKT signaling pathway, but not the MEK/ERK signaling pathway, and p21 expression in the human ovarian carcinoma cell line A2780. Furthermore, the cell death induced by cisplatin or paclitaxel seems to occur independently of these signal transduction pathways and p21 expression.
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Materials and Methods |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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-32P]dATP
was obtained from DuPont (New England Nuclear, Wilmington, DE).
Cell Culture, Drug Treatment, and Preparation of Cell Extract.
A2780, OVCAR-5, and OVCAR-10 cells were maintained in monolayer culture
as described elsewhere (15)
. Cells (2 x 105/well) were plated in 6-well plates and grown
overnight in RPMI 1640 containing 10% fetal bovine serum. In Fig. 1
, porcine insulin (0.25 units/ml) was supplemented in the cell culture
medium, as indicated in the figure legend. A2780 cells were incubated
with culture medium containing 10 µM cisplatin or 50
nM paclitaxel for 24 h. OVCAR-5 and OVCAR-10 cells
were incubated with culture medium containing 10 µM
cisplatin or 100 nM paclitaxel for 24 h. We verified
that in A2780 cells cisplatin or paclitaxel induces p53 and p21 in a
dose- and time-dependent manner (data not shown). To inactivate PI3K or
MEK1, 10 µM of LY294002 or PD98059, respectively, were
added to the medium 1 h before cisplatin or paclitaxel treatment
as indicated in the figure legends. We also confirmed that 10
µM of LY294002 or PD98059 is sufficient for specific
inactivation of PI3K/AKT- or MAPK-mediated signaling, respectively, in
A2780 cells (Fig. 1B
and data not shown). Whole cell
extracts were then prepared as described previously (16)
.
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cDNA Clones and DNA Transfection.
Plasmid DNA constructs for the expression of HA-epitope-tagged forms of
AKT (i.e., HA-Akt1, HA-AKT2, myrHA-Akt1, myrHA-AKT2, and
HA-AKT2E299K) were prepared as described previously (16)
.
The inactive Akt1 mutant HA-Akt1AA (threonine 308 and serine 473
replaced with alanines) was a gift from A. Bellacosa (Fox Chase Cancer
Center, Philadelphia, PA). Transfections were carried out with 2 µg
of plasmid DNA/2 x 105 cells,
using LipofectAMINE reagent. Note that the related human AKT proteins
are designated AKT1 and AKT2, whereas the murine protein homologous to
human AKT1 is designated Akt1.
Northern Blot Analysis.
A2780 cells (5 x 106) were
cultured in 150-mm dishes, followed by treatment with LY294002
dissolved in DMSO and chemotherapeutic agents, as described above.
Total cellular RNA was prepared by the guanidium isothiocyanate and
phenol/chloroform extraction procedure. RNA samples (25 µg) were
separated through 1% agarose gel and transferred onto nylon membranes
(Gene Screen; DuPont). Membranes were hybridized with
[-32P]dATP-labeled p53 or p21 cDNA probes.
Cytotoxicity Assay.
The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay
was used to determine the relative sensitivities of A2780 cells to
cisplatin and paclitaxel (17)
. Cells were plated in 150
µl of medium per well in 96-well plates (Corning Glass, Corning, NY).
Following overnight incubation, LY294002 and PD98059 were added to a
final concentration 10 µM each, and the plates were
incubated for 1 h. To determine the IC50
value, various concentrations of cisplatin or paclitaxel were then
added in a 10 µl volume. After a 72-h incubation, 50 µl of 5 mg/ml
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide were added
per well. After 2 h at 37°C, the cells were lysed by adding 100
µl of 20% (w/v) SDS, 50% (v/v) N,N-dimethylformamide, pH 4.7 and
incubated overnight at 37°C. The absorbance at 595 nm was measured
for each well using a Bio-Tek ELx800 microplate reader (Bio-Tek
Instruments, Winooski, VT).
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Results |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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, compare
Lanes 1 and 4), however, the induction of p21 in
response to cisplatin or paclitaxel was abrogated (Fig. 1A
,
Lanes 5 and 6). When A2780 cells were cultured in
the presence of insulin prior to serum starvation, they were still
capable of inducing p21 in response to cisplatin or paclitaxel
treatment (Fig. 1A
, Lanes 7–9). These data
suggest that the signaling activity in response to mitogenic
stimulation is required for maximal p21 induction. To determine the
relevant signal transduction pathway, we used inhibitors specific for
the pathway (i.e., the MEK1 inhibitor PD98059 and the PI3K
inhibitor LY294002). An anti-phospho ERK antibody that recognizes the
dual phosphorylated active forms of p44/ERK1 and p42/ERK2 was used to
analyze MAPK. As shown in Fig. 1B
, preinactivation of PI3K
by LY294002 partially inhibited p21 induction by cisplatin or
paclitaxel treatment (Lanes 3 and 7). On the
other hand, treatment with either cisplatin or paclitaxel activated the
MAPK signal transduction pathway (Fig. 1B
, Lanes
1, 2, 5 and 6), and the
phosphorylation of ERK was specifically inhibited by PD98059 (Fig. 1B
, Lanes 4 and 8). Preinactivation of
the MAPK signal transduction pathway by PD98059, however, had no effect
on p21 induction by either drug. These data indicate that PI3K, but not
MAPK, participates in regulating p21 expression in response to
cisplatin or paclitaxel treatment in A2780 cells.
Because previous studies have shown that in some instances the
BAX gene is also transactivated by p53 (21
, 22)
, we assessed the expression of BAX and p53 in cells treated
with cisplatin or paclitaxel. As shown in Fig. 1B
, PD98059
or LY294002 had little or no effect on the expression of BAX or p53 in
response to cisplatin or paclitaxel treatment. Marked up-regulation of
BAX expression by paclitaxel treatment was not observed in this
experiment, presumably due to differences in the mechanism of
cytotoxicity of cisplatin and paclitaxel (20)
. Overall,
these data indicate that PI3K participates in the regulation of p21
expression, but it is not required for BAX expression.
To determine whether the responses seen in A2780 cells are generally
applicable, similar experiments were performed with other human ovarian
carcinoma cell lines. Inhibition of p21 induction by the inactivation
of PI3K was observed in OVCAR-10 cells, which express wild-type p53,
whereas no significant alteration of p21 expression was observed in
OVCAR-5 cells, which lack p53 expression (Fig. 1C)
. Notably,
although there is significant induction of p53 by cisplatin or
paclitaxel treatment, a slight reduction in p53 expression was observed
in both A2780 and OVCAR-10 cells treated with LY294002 (Fig. 1, B and C)
. These data suggest that PI3K plays an
important role in p21 expression in cells expressing functional p53.
We next addressed whether PI3K is involved in p21 expression at the
transcriptional level. Northern blot analyses were performed using p21
and p53 cDNAs as probes. As shown in Fig. 1D
, although
neither cisplatin nor paclitaxel treatment altered the level of p53
mRNA, they did induce an increase in p21 mRNA expression, which was
partially suppressed by LY294002 treatment. Specifically, densitometric
analysis revealed that LY294002 treatment reduced p21 mRNA induction by
cisplatin and paclitaxel 
70% and 45%, respectively. Collectively,
our findings suggest that PI3K is required for full up-regulation of
p53 protein expression and plays a role in p21 induction at the
transcriptional level.
AKT Participates in Regulating p21 Expression.
We previously demonstrated that on insulin stimulation A2780 cells
activate the serine/threonine kinases AKT1 and AKT2 in a PI3K-dependent
manner (16)
. To assess the effect of AKT on p21
expression, HA-epitope-tagged wild-type Akt1 (HA-Akt1) or
constitutively active Akt1 (myrHA-Akt1) was expressed in serum-deprived
A2780 cells. Cells transfected with plasmid vector alone failed to
induce p21 due to serum starvation, whereas overexpression of HA-Akt1
sustained the drug-dependent p21 induction (see pcDNA3 and
HA-Akt1 in Fig. 2A
). Furthermore, cells transfected with myrHA-Akt1 showed
elevated levels of p21 expression (compare HA-Akt1 and
myrHA-Akt1). Parallel experiments with AKT2 constructs
showed similar results.
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, compare Lanes 1, 2, and
3 and Lanes 4, 5, and 6).
Thus, the expression of dominant negative AKT mutants mimicked the
effect of the PI3K inhibitor. Taken collectively, these data indicate
that both PI3K and AKT play a critical role in regulating the
expression of p21 in response to cisplatin and paclitaxel treatment in
A2780 cells.
Inactivation of PI3K/AKT Signaling Does Not Alter the Drug
Sensitivity of A2780 Cells.
We next addressed whether abrogation of p21 induction via inactivation
of PI3K affects the sensitivity of A2780 cells to cisplatin or
paclitaxel treatment. A2780 cells were incubated with LY294002 before
cisplatin or paclitaxel treatment. PD98059 was used for the comparative
control. As shown in Table 1
, neither LY294002 nor PD98059 affected the sensitivity of A2780 cells
to cisplatin and paclitaxel. We also confirmed that there was no
difference in the chemosensitivity of A2780 cells cultured in the
presence or absence of insulin (data not shown). In addition, A2780
cells stably expressing HA-Akt1 or HA-AKT2 did not alter the drug
sensitivity to cisplatin or paclitaxel (data not shown).
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Discussion |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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. Although treatment with either cisplatin or paclitaxel results in
increased p53 protein levels in A2780 cells, transcriptional levels of
p53 are not altered. Thus, the increases in p53 by these agents is
likely to occur by posttranscriptional regulation, possibly due to
enhanced protein stability (23)
. Our data demonstrate that
either inactivation of PI3K or expression of dominant negative AKT
inhibits p21 expression without significant effect on the regulation of
BAX expression in A2780 cells (Fig. 3)
. In addition, expression of
constitutively active or wild-type AKT enhanced p21 expression and
sustained p21 induction in response to drug treatment. Overall, the
data presented here demonstrate that PI3K and AKT are required for full
induction of p21 in response to cisplatin or paclitaxel.
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. On phosphorylation of Rb by cyclin-dependent kinases, Rb
dissociates from E2F, resulting in increased transcriptional activity
mediated by free E2F (25)
. Ectopic expression of cyclin D1
has been shown to induce p21 expression through activation of E2F
(26)
. Recently, PI3K/AKT signaling has been demonstrated
to stimulate induction of cyclin D1 expression (13)
and
also regulate several transcription factors, such as E2F,
cAMP-responsive element binding protein, and the Forkhead family member
Daf-16 (27, 28, 29)
. Thus, in addition to its role in
inhibiting apoptosis (10)
, the PI3K/AKT signal
transduction pathway seems to be involved in cell cycle control via the
synergistic regulation of cyclin D1 and E2F (Fig. 3)
. Moreover, protein
synthesis is another significant response to a variety of stimuli
in vivo. A critical event of protein synthesis is the
phosphorylation of eIF4E-binding protein 1 and its dissociation from
the mRNA cap binding protein eIF4E (eukaryotic translation initiation
factor 4E; Ref. 30
), leading to the activation of mRNA
translation. PI3K and AKT are involved in this process
(30)
and thereby may increase the efficiency of
translation of p21 mRNA. It is noteworthy that insulin stimulates the
phosphorylation of eIF4E-binding protein 1, which results in increased
insulin-dependent protein synthesis in a variety of cell types
(10)
. Therefore, we conclude that PI3K and AKT play a
potentially critical role in p21 expression at both the transcriptional
and posttranscriptional levels. Importantly, to ascertain the general
applicability of the A2780 data, we tested the response of other
ovarian carcinoma cell lines. These data demonstrated that cisplatin
and paclitaxel can induce p21 in cells retaining functional wild-type
p53, but not in cells that lack the functional p53 expression. The lack
of p21 induction in the latter cells is expected, given that p21 is a
downstream target of p53. These data suggest that p53-dependent p21
induction requires PI3K. On the other hand, overexpression of active
AKT in A2780 cells increased in the level of p21 expression without
drug treatment. Therefore, it is possible that AKT participates in the
regulation of both p53-dependent and p53-independent p21
expression. Future investigations will address this issue. Many oncogene and tumor suppressor gene products are components of signal transduction pathways that control cell cycle entry/exit, cell differentiation, DNA repair, cell survival/death, or stress response programs. Tumor promoter PMA induces p21 expression via ERK signaling in MCF-7 cells (14) , and we also confirmed that in A2780 cells p21 is induced by PMA treatment in a MAPK-dependent manner without up-regulation of p53 expression (data not shown). Thus, these data suggest that cells use alternative independent signal transduction pathways for p21 induction and that the involvement of PI3K/AKT in p21 induction is specific to the stress induced by cisplatin or paclitaxel.
We previously demonstrated that A2780 cells are sensitive to cisplatin
or paclitaxel treatment (15)
. However, little is known
about the mechanism of cell death induced by cisplatin or paclitaxel.
In the process of apoptosis, the release of cytochrome c
into the cytoplasm is required for the activation of procaspase-3 by
caspase-9 (31)
. It has also been demonstrated that Akt1
can phosphorylate and inactivate caspase-9 and suppress
caspase-9-induced apoptosis in 293 cells (32)
. However,
the cell death induced by cisplatin has been shown to proceed in a
caspase-3-independent manner in A2780 cells (33)
. In
addition, it has also been demonstrated that p21 is not required for
p53-dependent apoptosis because thymocytes from transgenic mice lacking
p21 genes are still capable of undergoing apoptosis after
irradiation (34)
. Our studies provide additional support
for these notions because alteration of p21 expression in A2780 cells
by inactivation of the PI3K/AKT signal transduction pathway did not
affect the sensitivity of cells in response to cisplatin or paclitaxel
treatment. These data suggest that although p21 induction may be
required to regulate the cell cycle as an emergency signal when cells
are exposed to chemotherapeutic drugs, the cell death programs
(including BAX expression induced by the drug) proceed independently
from the process of cell cycle control (Fig. 3)
. Thus, future studies
of the high drug sensitivity of A2780 cells may provide us with novel
insights into mechanisms of drug sensitivity with respect to
chemotherapy for the drug-resistant tumor cells.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by National Cancer Institute Grants
CA-77429, CA-51228, and CA-06927 and by an appropriation from the
Commonwealth of Pennsylvania. 
2 To whom requests for reprints should be
addressed, at Human Genetics Program, Fox Chase Cancer Center, 7701
Burholme Avenue, Philadelphia, PA 19111. Phone: (215) 728-2610; Fax:
(215) 728-2741.
3 The abbreviations used are: MAPK,
mitogen-activated protein kinase; ERK, extracellular signal-regulated
kinase; MEK1, MAPK kinase 1; PI3K, phosphatidylinositol 3-kinase; PMA,
phorbol 12-myristate 13-acetate; mAb, monoclonal antibody; HA,
hemagglutinin.
Received 1/18/00. Accepted 8/14/00.
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