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Advances in Brief |
Nelson Institute of Environmental Medicine, and Kaplan Comprehensive Cancer Center, New, York University School of Medicine, New York, New York 10016 [K. S., M. C.], and Medicine Branch, National Cancer Institute, NIH, Bethesda, Maryland 20892 [W. D. F. and M. V. B.]
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ABSTRACT |
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expression vector induced transcription from
p21 promoter construct in prostate cancer cell lines. Furthermore,
hypoxia slightly induced p21 mRNA in these cells. However, neither
expression of p21 nor hypoxia caused growth arrest in PC-3M cells.
Therefore, high inducibility of HIF-1-dependent genes, loss of p53
functions with high ratio of HIF-1-dependent:p53-dependent
transcription, and loss of sensitivity to p21 inhibition is a part of
hypoxic phenotype associated with aggressive cancer behavior. |
Introduction |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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Taking into account that hypoxia, while limiting tumor growth, is inevitably associated with tumor progression, we envision the ability of cancer cells to survive hypoxia as a natural test that on successful completion allows further tumor progression. We propose that the adverse conditions associated with hypoxia provide a driving force for selection of aggressive, autonomous, and metastatic phenotypes. Interestingly, hypoxia and carcinogenic nickel exert almost identical effects on gene expression. Furthermore, nickel, a potent nonmutagenic carcinogen, induces gene expression, in part through HIF-1 transcription factor (8 , 9) .
Previously, we have demonstrated an increase in HIF-driven
transcription versus a p53-driven transcription in
nickel-transformed cells (8)
. If hypoxia plays a
significant role in tumor progression, we predict that not only
nickel-transformed cells but also natural human cancer cells would have
HIF-1:p53 alterations. In fact, Zhong et al.
(10)
have demonstrated that elevated amounts of HIF-1
protein exist in PC-3 prostate cancer cells under normoxic conditions
linking HIF-dependent transcription under normoxia with tumor
progression (11)
. Here we evaluated HIF-1- and
p53-dependent transcription in a panel of prostate cell lines ranging
from normal PrECs to the most aggressive PC-3M cells, previously
selected for increased metastatic potential in mice. The comparison of
PC-3M cells with less aggressive cells revealed more pronounced
"hypoxic" features of the aggressive cancer phenotype. Because
hypoxia already exists in primary prostate carcinomas
(12)
, our data suggest that an increased inducibility of
HIF-dependent genes may be a hallmark of the hypoxia-driven selection.
Furthermore, we have shown that rather high levels of HIF-1 are
required for transcriptional activation of
p21waf1/cip1. This activation occurs in prostate
cancer cells in a p53-independent manner. The accumulation of p21 did
not result in growth arrest in either PC-3M or DU-145 cells. Using flow
cytometry, we have shown that prostate cancer cells lost their
p21-dependent cell cycle control, whereas p53-dependent cell cycle
control was still intact in these cells.
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Materials and Methods |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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Plasmids and Transient Transfection.
WWP-Luc, a p21 promoter-luciferase construct, was obtained from Dr.
W. S. El-Deiry (University of Pennsylvania). Bax-Luc, a Bax
promoter-luciferase construct was obtained from K. Vousden (ABL Basic
Research Program, NCI-FCRDC).
pC53-SN3, containing wt p53 in a pCMV-Neo-Bam vector, was obtained from Dr. B. Vogelstein (Johns Hopkins University Baltimore, MD). pCMVb.HA-HIF-1a expression plasmid was obtained from Dr. D. Livingston (Dana-Farber Cancer Institute, Boston, MA). pCMV.ß-galactosidase was purchased from Clontech (Palo Alto, CA). GFP-expressing plasmid was obtained from Promega.
A HIF-responsive, VEGF promoter-derived luciferase construct containing four amplified HIF-1 binding sites (VEGF-Luc), inserted into a pGL2-promoter vector (15) was obtained from A. J. Giaccia (Stanford University, Palo Alto, CA). A partial VEGF promoter (p7) Luc construct was described previously (4) and obtained from Dr. G. Semenza (John Hopkins University, Baltimore, MD). A HIF-responsive, erythropoietin promoter-derived luciferase construct (Epo-Luc) inserted into a pGL3-Promoter vector was obtained from F. Bunn and E. Huang (Harvard Medical School, Boston, MA). A HIF-1 responsive element promoter luciferase construct (NOS-Luc or HRE-Luc), a gift from Dr. G. Melillo (National Cancer Institute), was described previously (8) .
A total of 50,000 cells were plated in 24-well plates and, on the next day, were transfected with plasmids using Lipofectamine (Life Technologies, Inc.) or TransFast Transfection Reagent (Promega) according to the manufacturers’ recommendations. After 2–6 h of incubation with the plasmid-lipid suspension, the medium was changed, and cells were grown for an additional 16 h, unless otherwise indicated; then cells were lysed and analyzed for luciferase activity. For inducing HIF-1 transcription factor, cells were incubated with 260 µM DFX as described previously (8) or at 1% oxygen (hypoxia). All of the measurements were performed in duplicate.
Immunoblot Analysis.
Proteins were harvested in TNESVF buffer [50 mM Tris-HCl
(pH 7.5), 2 mM EDTA, 100 mM NaCl, 1
mM sodium ortovanadate, 10 mM sodium fluoride,
and 1% NP40) with protease inhibitors. For HIF-1 protein, nuclear
extract was prepared as described previously (8)
. Equal
amount of proteins were resolved on 7.5% SDS-PAGE for HIF-1
(8)
. Immunoblot was performed using anti- HIF-1
antibodies (Lab Vision, Fremont, CA).
DNA Synthesis.
DNA synthesis was monitored by [3
H]thymidine
incorporation as described previously (14)
. In brief,
2,000 cells were plated in 96-well flat-bottomed plates, or 15,000
cells were plated in 24-well plates. The next day, cells were incubated
under either normoxic or hypoxic conditions (1% oxygen) for 24 h
and then were incubated with 1 µCi
[methyl-3
H]thymidine (Amersham) for an
additional 4 h after which, acid-insoluble radioactivity was
determined.
Cell Cycle Analysis.
Cells were harvested by trypsinization, washed with PBS, and
resuspended in 75% ethanol in PBS and kept at 4°C for at least 30
min. Before analysis, cells were washed again with PBS, resuspended,
and incubated for 30 min in propidium iodide staining solution
containing 0.05 mg/ml propidium iodide (Sigma), 1 mM EDTA,
0.1% Triton X-100 and 1 mg/ml RNase A in PBS. The suspension was then
passed through a nylon mesh filter and analyzed on a Becton Dickinson
FACScan.
For cell cycle analysis of GFP-transfected cells, PC-3M were
transfected with a vector-expressing GFP and cotransfected with vectors
expressing either wt p53 or HIF-1 or with an empty vector. Cells
expressing GFP were analyzed on a Becton Dickinson FACScan. Cells were
excited at 488 nM; GFP and propidium iodide were measured
at 520 nM and 585 nM, respectively. Cell cycle
analysis was performed on 520-nM-positive cells.
Northern Blotting.
Total RNA was extracted from cells immediately after treatment using
RNAzol B (Cinna/Biotek) and following manufacturer’s instructions,
electrophoresed (15–20 µg of total RNA/lane) in 1.2%
agarose/formaldehyde gels, and transferred to a nylon membrane in 7.5
mM NaOH buffer overnight. Probes representing a coding part
of GAPDH or p21, or Cap43 gene were labeled with
[-32P]dCTP using a Random Primed DNA
Labeling kit (Boehringer Mannheim). The membrane was prehybridized for
2 h, hybridized with the probe for 2 h, washed, and exposed
to Kodak X-ray film overnight (9)
.
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Results |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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). We observed several trends in the expression of these
HIF-1-responsive constructs. First, basal expression of HIF-1-dependent
constructs was very high in PC-3M, even compared with PC-3, cells and
were the lowest in PrEC and LNCaP cells. Thus, the comparison of PC-3
cells with their highly metastatic subclone (PC-3M) demonstrates
several-fold elevation in the basal levels of HIF-dependent
transcription in PC-3M. Second, the inducibility of HIF-responsive
constructs was minimal in PrEC but was high in all prostate cancer
cells, including LNCaP, PC-3, PC-3M (Fig. 1A)
, and DU-145
(data not shown). Like the basal expression, the induced expression of
the HIF-1-responsive reporter constructs was especially high in PC-3M
cells.
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. Therefore, in
contrast to cancer cells, normal prostate epithelial cells display
testosterone-dependent rather than hypoxia-dependent regulation of
Cap43. Basal levels of the GAPDH and
Cap43 mRNA were higher in PC-3M and PC-3 cells than in LNCaP
cells (Fig. 1B)
. Hypoxia induced expression of
Cap43 in all cancer cell lines, particularly in PC-3 and
PC-3M (Fig. 1B)
. Inducibility was much weaker for
GAPDH than for Cap43. This indicates that
Cap43 is very sensitive to hypoxia, whereas GAPDH, which
encodes a glycolytic enzyme, is more constitutively expressed. Although
the expression of the hypoxia-responsive genes under normoxic
conditions did not differ dramatically in all of the cell lines, the
inducible levels correlated with tumor progression. The induced levels
of mRNA of these genes including GAPDH was the highest in
PC-3M cells (Fig. 1B)
. In fact, exposure to hypoxia
especially strongly stimulated acidification of the culture
medium by PC-3M cells, reflecting high induction of glycolytic enzymes.
Comparison of PC-3 and Highly Metastatic PC-3M Cells.
Previously we found that a ratio of HIF-dependent:p53-dependent
transcription is increased in the nickel-transformed cells
(8)
. Here we calculated the ratio of HRE-Luc
(HIF-dependent):WWP-Luc (p53-dependent) transcription in prostate cell
lines. We found that an increased ratio of HRE-Luc expression:WWP-Luc
expression, especially under hypoxia, was a marker of the advanced
cancer cell lines (Fig. 1C)
.
The high ratio in PC-3 and PC-3M cells is in part determined by
mutations in p53 in PC-3 and PC-3M. However, even in these two cell
lines (with a similar background and p53 status) a higher ratio
correlated with a higher metastatic potential of PC-3M. We further
compared these two cell lines (Fig. 2A)
. Under hypoxic conditions, PC-3M cells had higher levels
of expression of VEGF-Luc, Epo-Luc, HRE-Luc (Fig. 2A)
as
well as of HIF-1 protein (Fig. 2C)
than PC-3 cells.
Importantly, expression not only of HIF-dependent constructs but also
of p21 promoter Luc construct (WWP-Luc) was higher in metastatic PC-3M
than in PC-3 cells (Fig. 2B)
. This indicates that an
increased ratio of HIF-dependent transcription:p53-dependent
transcription (shown in Fig. 1C
) is not a result of
down-regulation of p21 expression. In contrast to p21, expression of
another p53-dependent promoter, namely Bax, was not increased in PC-3M
cells (Fig. 2B)
.
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gene
(9)
grow faster than wt MEF cells, with doubling time of
1.2 days versus 2.8 days, respectively. Hypoxia slightly
induced p21 mRNA in these cells (data not shown); however, the wt p53
status of MEF cells precludes firm conclusions.
Here we demonstrate that transient transfection of HIF-1-expressing
vector induced p21-promoter-Luc construct in PC-3M and DU-145 cells,
which lack wt p53 (Fig. 2D)
. This is the first direct
evidence that HIF-1 can transactivate p21 promoter. A dose-dependent
response demonstrates that HIF-1-expressing plasmid should be
transfected in excess of p21-promoter construct to achieve its
activation (data not shown), which indicates that a very high level of
HIF-1 is required for p21-Luc activation.
Hypoxia slightly induced the p21 mRNA in these cell lines (Fig. 3A)
supporting the notion that HIF-1 might be involved in
p21-dependent inhibition of growth of normal cells (17)
.
Nevertheless, hypoxia did not inhibit the proliferation of prostate
cancer cells, as evidenced by unchanged
[3
H]thymidine incorporation immediately after
hypoxia (Fig. 3A
, bar graphs).
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or p53 expression vectors, or infection
with p21 adenovirus. For flow cytometry analyses, cells were
cotransfected with GFP-expressing plasmid to mark and analyze
only transfected cells. Sub-G1 peaks
observed in these experiments reflected toxicity that resulted
from transient transfections with lipofectamine (Fig. 3B)
.
The cells transfected with HIF-1 did not differ from the cells
transfected with empty vector only (control). In contrast, transfection
with wt p53 induced G1 phase arrest in PC-3M
cells (Fig. 3B)
. Interestingly, the infection with
Ad-p21-expressing p21 did not induce growth arrest in PC-3M
cells (Fig. 3B)
, which suggests that, downstream, components
of the p21-inhibitory pathway are impaired in these cells.
Importantly, hypoxia was accompanied by acidosis. It is not
surprisingly that, in a high cell density, hypoxia caused acidification
of the culture medium because of lactic acid production. Such acidosis
induced G2 phase cell cycle arrest in PC-3M cells
(Fig. 3C)
, with similar G2 arrest
caused by lactic acid without hypoxia (data not shown).
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Discussion |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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We previously observed an increased ratio of HIF-driven transcription to p53-driven transcription in nickel-transformed cells (8) . Here we described a hypoxic phenotype of prostate cancer cells with high inducibility of a HIF-dependent transcription, accompanied by the loss of wt p53 function and a low p53-dependent transcription. In brief, HIF-1 substitutes for p53, as a stress regulator, in highly metastatic prostate cancer cells.
Zhong et al. have described detectable expression of
HIF-1 protein in normoxic conditions (10)
, which leads
to the notion that the increased HIF-dependent transcription is
accompanying tumor progression. Here we found that in normal prostate
epithelial cells, hypoxia only slightly affected two hypoxia-regulated
genes, Cap43 and GAPDH, but dramatically
increased their expression in cancer cells, further providing evidence
that the increased HIF-dependent transcription is a part of
tumor progression. Additionally, aggressive behavior corresponded to
higher expression of HIF-responsive constructs in PC-3M and to very
high ratio of HIF-1-dependent:p53-dependent transcription. Although p53
mutations in primary prostate cancer are relatively infrequent, they
often occur at later, metastatic stages of the disease
(20)
; therefore, prostate cancer progression indeed
involves p53 inactivation (21)
.
Growth control is impaired in prostate cancer. Recently, p21 was shown
to be significantly expressed in highly proliferating prostate tumors
but not in normal or hyperplastic prostate epithelium
(22)
. The expression of p21 did not correlate with wt p53,
which suggests that other factors were involved in p21 up-regulation.
Here we tested the direct ability of HIF-1 to activate p21 promoter
construct and effects of hypoxia on p21 mRNA expression in p53-mutated
prostate cancer cells. Indeed, we found that p21 is transactivated by
HIF-1. The p21 promoter contains ACGTG sequence, which has been
implicated in the regulation of lactate dehydrogenase A by hypoxia
(23)
. Interestingly, HIF-1-null MEF cells grow faster than
wt cells, which indicated that HIF-1 may inhibit proliferation. It has
been shown that hypoxia failed to induce p21 in cells lacking HIF-1 but
induced p21 in parental cells (17)
. However, both cell
lines have wt p53, and, therefore, p21 induction can be attributed to
wt p53 function. In this study, we found that hypoxia up-regulated p21
mRNA in DU-145 and PC-3M, both of which are cell lines with mutated
p53. However, neither a high level of HIF-1 protein nor hypoxia
arrested cell growth, which suggests that induction of p21 is
dissociated from growth arrest in the advanced prostate cancer cells
(Fig. 4)
. Similarly, despite the induction of p21, phorbol ester did not cause
growth arrest in PC-3M, PC-3, or DU-145 cells (13)
but
caused p21-mediated growth arrest in LNCaP and PrEC. Our data are in
agreement that 88% of prostate cancers have a high level of p21 that
is dissociated from growth arrest (22)
. Furthermore,
whereas HIF-1 negatively regulates the growth of normal fibroblasts
(17)
, it is required for solid tumor growth independently
of VEGF production (24)
. We conclude that the loss of
growth-inhibitory components downstream of p21, along with increased
HIF-1-dependent transcription, is a characteristic of aggressive
metastatic phenotype in prostate cancer (Fig. 4)
.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported in part by NIH Grants ES05512,
ES00260, and CA16087 ( to K. S. and M. C.). 
2 To whom requests for reprints should be
addressed, (to K. S.) at Nelson Institute of Environmental Medicine,
Kaplan Comprehensive Cancer Center, New York University, New York, NY
10016. Fax: (914) 351-2118; E-mail:salnikow{at}env.med.nyu.edu; or (to
M. V. B.) at Medicine Branch, Building 10, R 12N226, NIH, Bethesda,
MD 20892. Fax: (301) 402-0172; E-mail: mikhailb{at}box-m.nih.gov
3 The abbreviations used are: HIF-1,
hypoxia-inducible factor; VEGF, vascular endothelial growth factor;
PrEC, prostate epithelial cell; DFX, desferrioxamine; wt, wild type;
GFP, green fluorescent protein; GAPDH, glyceraldehyde-3-phosphate
dehydrogenase; CMV, cytomegalovirus.
Received 5/10/00. Accepted 8/29/00.
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REFERENCES |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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is required for solid tumor formation and embryonic vascularization. EMBO J., 17: 3005-3015, 1998.[Medline]
in rat and human prostate cancer. Cancer Res., 58: 5280-5284, 1998. in common human cancers and their metastasis. Cancer Res., 59: 5830 5835, 1999.
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