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Reproductive Biology Unit (J.L., Q.F., J.-M.K., D.S., M.L., B.V., B.K.T.) and Division of Gynecologic Oncology (B.V., W.F., M.F.K.F., M.S., B.K.T.), Departments of Obstetrics and Gynecology, Cellular and Molecular Medicine (J.L., D.S., B.V., B.K.T.) and Pathology (M.S.), University of Ottawa; Loeb Health Research Institute (J.L., Q.F., D.S., J.-M.K., M.L., B.K.T.), The Ottawa Hospital (W.F., M.F.K.F., M.S., B.K.T.), ApoptoGen, Inc. (P.L., R.G.K.), and Children’s Hospital of Eastern Ontario, Ottawa Regional Cancer Center (B.V.), Ottawa, Ontario, Canada K1Y 4E9
Address all correspondence and requests for reprints to: Benjamin K. Tsang, Ph.D., Loeb Health Research Institute, The Ottawa Hospital (Civic Campus), 725 Parkdale Avenue, Ottawa, Ontario, Canada K1Y 4E9. E-mail: btsang{at}lri.ca
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Apoptosis plays an important role in the maintenance of physiological homeostasis in response to stimuli that indicate that a cell is potentially harmful or abnormal (4, 5, 6). When the apoptosis machinery fails, abnormal cells can survive, and unopposed tissue growth, as in the case of cancer, can result. Thus, it is conceivable that carcinomas may be caused or promoted in part by factors inhibiting cell death. In this regard, considerable work has been focused on the role of bcl-2 (7, 8, 9) as a negative regulator of apoptotic cell death (10). In ovarian cancer, expression of the bcl-2 gene is an important modulator of drug-induced apoptosis and a potential determinant of chemoresistance (8) and survival (9). However, evidence also indicates that bcl-2 overexpression or mutation cannot adequately account for the etiology of existing ovarian cancer (7, 11), suggesting that other cell survival factors may also be involved in this complex process.
Inhibitor of apoptosis proteins (IAPs) were first identified in baculoviruses, where they function to keep the host cell alive while the viruses replicate (12, 13). Five IAPs have recently been identified in mammalian cells: neuronal apoptosis inhibitory protein (Naip) (14), X-linked inhibitor of apoptosis protein (Xiap) (15, 16, 17), human inhibitor of apoptosis protein-1 (Hiap-1) (15, 16, 18), Hiap-2 (15, 16, 18), and survivin (19). The apoptosis-suppressive actions of mammalian IAPs have been previously shown. For example, the overexpression of IAPs, including Naip, Xiap, Hiap-1, and Hiap-2, protects Chinese hamster ovary (CHO) and Rat-1 cells from apoptosis triggered by menadione, a potent inducer of free radicals, or by growth factor withdrawal (15). Overexpression of Xiap or Hiap-2 protected HeLa cells from apoptosis induced by transient transfection of prointerleukin-1ß-converting enzyme (16), and Xiap was shown to suppress apoptosis induced by Sindbis virus (17). In most of these studies, the protection mediated by the IAPs was comparable to that mediated by known antiapoptotic proteins, such as Bcl-2.
In the present study we examined the possible role of IAPs in the regulation of apoptosis in hOSE cancer cells and the possible involvement of these proteins in the action of the chemotherapeutic agent cisplatin and in chemoresistance. This communication represents the first report supporting an important role for Xiap in chemoresistance in human cancer.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Adenoviral infection
After 24 h of plating, OV2008 and C13 were infected with an
adenoviral Xiap or Hiap-2 sense or antisense at a multiplicity of
infection (MOI) of 5 or 10. The infection efficiency at a MOI of 5,
evaluated by X-galactosidase test, was approximately 90% for both cell
lines. Cells were either infected with adenoviral sense Xiap
complementary DNA (cDNA; MOI = 5) for 48 h before the
addition of cisplatin or for 60–72 h with the adenoviral Xiap
antisense (MOI = 5 and 10). To prepare the adenoviral expression
vectors for the full-length sense and antisense cDNAs of Xiap and
Hiap-2, the open reading frames (ORFs) of Xiap and Hiap-2 were PCR
amplified with primers corresponding to the amino- and
carboxyl-termini. These PCR products were cloned in the pCR2.1 vector
(Invitrogen, San Diego, CA), and sequenced. The ORFs were
cut out with EcoRI, blunt ended with Klenow fragment of DNA
polymerase I, and ligated into Swa-1-cut pAdex1CAwt cosmid
DNA. Packaging was performed with the Promega Corp. cosmid
packaging extracts (Madison, WI) and used to infect Escherichia
coli. Colonies were picked and screened for the presence of the
insert in both the sense and antisense orientations relative to the
chicken ß-actin promoter. CsCl-purified cosmid DNA was cotransfected
with wild-type adenovirus DNA that contains the terminal protein
complexed to the ends of the DNA. Wild-type adenovirus DNA was cut with
Nsi-1, such that only homologous recombination with the
cosmid DNA will generate infectious adenovirus DNA. The final
recombinant adenovirus contains a linear, double stranded genome of
44,820 bp plus the insert size (
1500 bp for Xiap, 1800 bp for
Hiap-2). This method has been shown to be an efficient means of
generating recombinant adenoviruses (31).
Western blot
Total cell protein extracts were prepared as follows. Cells were
sonicated (8 sec/cycle, three cycles) on ice in 10 mM HEPES
buffer (pH 7.4) containing 1 mM EGTA and 2 mM
phenylmethylsulfonylfluoride. The sonicates were stored at -20 C until
electrophoretic analyses were performed. Protein concentration was
determined by protein assay (Bio-Rad Laboratories, Inc.,
Richmond, CA). Equal amounts of proteins (60–80 µg, depending on
individual experiments) in cell extracts were resolved by SDS-PAGE and
transferred to nitrocellulose membrane (32). Membranes
were blocked with 5% nonfat milk and subsequently incubated with
rabbit polyclonal antihuman Xiap or Hiap-2 antibody (1:2000 and 1:1000
dilutions, respectively). An ECL kit (Amersham Pharmacia Biotech) was used to visualize immunopositive proteins. To
ascertain whether protein loading to each lane was even within each
acrylamide gel, the overall protein bands in the gels were routinely
stained with Coomassie blue after electrotransfer and analyzed
densitometrically for staining intensity. Results from experiments with
uneven protein loading were excluded in the final analysis.
To generate polyclonal antibodies for the present studies, full-length
Xiap- or Hiap-2-coding regions were ligated into the pGEX
(Pharmacia-LKB, Piscataway, NJ) vector system and
expressed as glutathione-S-transferase (GST) fusion proteins
in Escherichia coli. The recombinant proteins were affinity
purified using glutathione-Sepharose and used to immunize New Zealand
White rabbits. Fifty micrograms of protein were suspended in 0.6 ml
RIBI adjuvant (Sigma, St. Louis, MO) and injected in
0.1-ml aliquots at each of six sites. Rabbits were injected weekly for
4 weeks, at which point harvesting of serum was initiated. Antibody was
affinity purified using a GST-Xiap or GST-Hiap-2 glutathione-Sepharose
column containing a minimum of 400 µg recombinant protein. Depleted
antibody was prepared by passing the affinity-purified antibody over
the same column and collecting the flow-through. Studies on the
specificity of these antibodies indicated that absorption of the
respective antibody on affinity columns effectively ablated the signals
of the IAP proteins on Western blots and that no cross-reactivity with
other IAPs was evident (Fig. 1
). The use
of rabbits in the generation of the antibodies was approved by the
University of Ottawa animal care committee and was in compliance with
the Guide to the Care and Use of Experimental Animals of the Canadian
Council on Animal Care.
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Preparation of hOSE carcinomas, immunohistochemistry, and in situ
localization of apoptotic cells
Samples of hOSE carcinomas were obtained fresh as
pathological specimens from three patients undergoing their initial
laparotomy for surgical staging and tumor debulking. The patients
(56–76 yr old) had stage III (disseminated intraabdominal) disease,
but no previous chemotherapy (Table 1).
The tumor tissues were fixed and paraffin embedded by routine
procedures. Xiap, Hiap-2, and proliferating cell nuclear antigen (PCNA;
an auxiliary protein of DNA polymerase 
highly expressed at the
G1/S interphase) was immunolocalized as
previously reported (32). Briefly, the tumor sections were
incubated in series with
H2O2, normal goat serum,
and rabbit polyclonal antihuman Xiap (0.5 µg/ml), Hiap-2 (0.5
µg/ml), or mouse monoclonal antihuman PCNA (0.5 µg/ml; Santa Cruz Biotechnology, Inc., Santa Cruz, CA) antibodies. Control
tumor sections carried out with the omission of the primary antibody
exhibited negative immunostaining. Immunoreactivities were detected by
a Vector ABC Elite Kit (Vector Laboratories, Inc.,
Burlingame, CA). Terminal deoxynucleotidyl transferase-mediated
dUTP-biotin end labeling (TUNEL) was performed as described previously
(33). Briefly, tumor sections were incubated in series
with proteinase K, H2O2,
and terminal deoxynucleotidyltransferase plus biotinylated
16-deoxy-UTP. The incorporated deoxy-UTP molecules were visualized with
horseradish peroxidase-conjugated streptavidin and
diaminobenzidene.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, top left panel). Although there also appeared to be a slight
increase in percentage of dead cells with Hiap-2 antisense infection,
it was not statistically significant (Fig. 2, top left
panel; P > 0.05). Infection of the
cisplatin-resistant variant of OV2008 cells (C13) with antisense of
Xiap, but not of Hiap-2, also significantly, although to a lesser
extent, decreased cell viability (Fig. 2, top right panel).
The cell death induced in both OV2008 and C13 by Xiap antisense was
also accompanied by decreases in total cell number (Fig. 2, bottom panels). The decrease in cell number could not be
completely accounted for by increased cell death, as Xiap antisense
infection (especially at MOI = 10) produced more cell death in
OV2008 than C13, whereas the total cell numbers for both cell lines
were similar. In addition, although Xiap antisense infection (MOI
= 5) failed to significantly induced cell death in C13 cells
(2.5%), it suppressed cell growth by 25% (P <
0.001). These findings suggest that ovarian epithelial cancer cell
proliferation may possibly be also under the regulation of Xiap and
that this response may be attenuated by Xiap down-regulation.
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, b, black arrows) and
nuclear fragmentation (white arrows), and
increased the number of apoptotic cells as well as the abundance of
apoptotic bodies (Fig. 3B, b and d compared with a and c). ANOVA
indicates that there were highly significant effects of the antisense
on Xiap protein content (P < 0.01; Fig. 3, D and E)
and apoptosis (P < 0.001; Fig. 3C). Indeed, infection
of these cells with a higher titer of the adenoviral antisense
(MOI = 10) further increased the number of cells undergoing
apoptosis (Fig. 3C).
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), and was accompanied by decreased IAP
contents (Fig. 5). The increase in
apoptotic cell number in response to cisplatin was concentration
dependent and significant (50% vs. 2%; P
< 0.05) even at a concentration of 10 µM
cisplatin (Fig. 4B). However, cisplatin failed to induce apoptosis in
C13 cells in this concentration range (Fig. 4B). In addition,
time-course studies on the induction of apoptosis by cisplatin in both
cell lines indicated that although OV2008 cells were responsive
[apoptotic cells, <20% (6 h), 45% (12 h), and 80% (24 h)]
to the anticancer agent (30 µM), it had no
significant effect on its resistant variant (C13; <2% at all times)
regardless of the culture period.
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, although both Xiap and Hiap-2 are present in
this cisplatin-sensitive hOSE cancer cell line (55 and 68 kDa,
respectively), their cellular contents were decreased by cisplatin in a
concentration-dependent manner, with Xiap appearing more responsive to
the anticancer agent. Although the Xiap level was decreased by almost
80% (P < 0.01) in the presence of 20
µM cisplatin, the decrease in Hiap-2 protein
content was not statistically significant at concentrations lower than
30 µM. However, the expression of Xiap and
Hiap-2 in C13 (the cisplatin-resistant variant of OV2008) was not
suppressed by cisplatin (Fig. 5), and no morphological characteristics
of apoptosis could be detected (Fig. 4A). Although Xiap and Hiap-2
contents in C13 appeared to be higher in the presence of the anticancer
agent, the differences were statistically nonsignificant
(P > 0.05). Time-course experiments on IAP expression
demonstrated that the suppression of Xiap and Hiap-2 protein levels in
OV2008 by cisplatin was time dependent; a significant decrease was
observed between 12–24 h of culture (Fig. 6). Expression of the IAPs in C13 cells
was not influenced by cisplatin regardless of the duration of
treatment.
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). Interestingly, whereas the Hiap-2
content in both the sensitive and resistant cells was not significantly
altered by the presence of the cisplatin, the level of Xiap was
markedly decreased in A2780s, but not in A2780cp (as in OV2008 and C13
cells), in the presence of the chemotherapeutic agent at 30
µM (Fig. 7). Although cisplatin significantly
increased the incidence of apoptosis in the resistant cells, and the
response was higher than that observed in C13 cells under identical
conditions, it was considerably lower than that of its
cisplatin-sensitive counterpart (OV2008; 7% vs.
50%). Taken together, these data suggest that the apoptotic
responsiveness of ovarian cancer cells to cisplatin may be related to
the ability of the chemotherapeutic agent to down-regulate Xiap
expression and that Hiap-2 may play a minor role or no role in
cisplatin-induced apoptosis.
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). Although cisplatin reduced Xiap
protein content in OV2008 cells infected with adenoviral LacZ (control
vector; LacZ + cisplatin), overexpression of the protein with
adenoviral sense Xiap cDNA 48 h before treatment with the
chemotherapeutic agent in vitro attenuated the cisplatin
effects not only on Xiap protein expression (Fig. 8, C and D), but also
on apoptotic nuclear fragmentation (Fig. 8A, d compared with c, and
Fig. 8B), suggesting that Xiap may be an important element in hOSE
cancer chemoresistance.
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). In addition, in situ TUNEL and
immunohistochemistry for PCNA (an auxiliary protein of DNA polymerase
highly expressed at the G1/S interphase) were
performed to examine whether and how the expression of these IAPs
relates to epithelial cell apoptosis and/or proliferation. As shown in
Fig. 9, which illustrates these
parameters from one patient (OC-4), ovarian epithelial tumors
exhibit considerable cellular heterogeneity, and PCNA-positive
cells were evident in cell nuclei throughout the tumor section. In
general, most of the cells were TUNEL negative, and the expression of
IAPs was highly correlated to the proliferative state of the cells and
inversely related to epithelial cell death. Xiap and Hiap-2
immunoreactivity (Fig. 9), specifically localized in cytoplasm or
perinuclear region, was highest in proliferatively active
(PCNA-positive) cells and was low or absent in the apoptotic
(TUNEL-positive) cells occasionally found in the tumor specimens.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A decrease in ovarian epithelial cancer cell number was observed after
Xiap down-regulation and could not be fully accounted for by increased
apoptosis, suggesting that Xiap may also important in the control
cancer cell growth. The dual roles of regulators in controlling cell
proliferation and apoptosis have been reported. For example,
transforming growth factor- and PGs have been shown to be both
mitogenic and antiapoptotic in ovarian granulosa cells (38, 39). Interestingly, down-regulation of survivin, another member
of the IAP family, can also induce apoptosis and suppress cell
proliferation in HeLa cells (40). Whether and how Xiap is
involved in the mitogenic signaling in human ovarian epithelial cancer
cells remain to be elucidated.
The cytotoxicity of cisplatin is believed to be due to its role in the formation of DNA adducts, including DNA-protein cross-links, DNA monoadducts, and interstrand DNA cross-links (41, 42), and its ability to trigger apoptosis. Apoptosis induced by cisplatin can be inhibited by cycloheximide, suggesting that synthesis of new proteins may be required (43, 44). However, the events that link DNA damage to the cell death pathway are not known. In the current study the concentration-dependent induction of apoptosis in OV2008 by cisplatin is accompanied by decreases in Xiap and Hiap-2 protein content, suggesting that the modulation of IAP expression and/or stability may be one of the mechanisms by which cisplatin induces apoptosis in the chemo-sensitive cells. This decrease in IAP levels did not appear to be due to a general cytotoxic effect of the anticancer agent, because studies carried out in our laboratory under identical experimental conditions have shown that the cisplatin treatment increased Fas and Fas ligand expression (28). Moreover, DNA damage-inducible genes, such as gadd153, gadd45, p21, and c-jun, have also been shown to be up-regulated by cisplatin in this cell system (25), suggesting that the observed decrease in IAP content was not a nonspecific response to cisplatin. In the present study we observed that whereas approximately 80% of OV2008 cells underwent apoptosis in the presence of cisplatin (30 µM), only 35–55% of the cell population were apoptotic when Xiap expression was down-regulated by antisense expression. Although the reasons for this apparent discrepancy remain to be determined, it is possible that cisplatin may have multiple points of action in the induction of cell death. For example, in addition to suppressing IAP expression, cisplatin has been shown to up-regulate the expression of a number of apoptosis inducers, including p53 (45), Fas, and Fas ligand (28). In the latter context, cisplatin (30 µM) significantly increased cell-associated Fas (300% over the control value) and Fas ligand (50% over the control value) as well as soluble Fas ligand (300% over the control value) in cisplatin-sensitive cells (OV2008) during a 24-h culture period (28). Alternately, the relatively low incidence of apoptosis could be due to insufficient Xiap down-regulation, as the antisense was only able to suppress Xiap by about 50%. In addition, in light of the fact that only one apoptosis suppressor (i.e. Xiap) was down-regulated in the antisense infection experiments (which only partially suppressed Xiap protein levels), it is not surprising that cisplatin was more effective in inducing cell death compared with the adenoviral Xiap antisense expression.
The relative importance of various IAP members in controlling hOSE cancer cell apoptosis is unclear. In addition to the slightly higher concentration of cisplatin required to down-regulate Hiap-2 than Xiap (30 vs. 20 µM) in OV2008 cells, our present studies demonstrated that adenoviral Hiap-2 antisense infection of OV2008 cells failed to significantly induce cell death. Although it is possible that only a minimal level of Hiap-2 is required to prevent the cells from undergoing apoptosis, a more likely possibility could be that Hiap-2 is less important or is unrelated to the regulation of ovarian epithelial cancer cell apoptosis. The latter is consistent with the present observation that Hiap-2 protein in A2780cp cells content not only was not decreased by cisplatin treatment, but appeared slightly, although not significantly, elevated. Further studies including double IAP antisense expression are required to clearly define the relative roles of the different IAP family members as well as their mechanisms of action in ovarian carcinoma.
Chemoresistance is a major therapeutic problem, and understanding the molecular mechanisms involved is a major focus for cancer research. The biology of chemoresistance has traditionally been thought of in terms of altered drug delivery, modified drug target, increased rate of DNA repair, or decreased rate of drug-induced DNA or macromolecule damage (45) as well as enhanced replicative bypass of platinum-DNA adducts in the resistant cells (46). Although recent evidence has suggested that drug resistance may in part be attributed to decreased cellular susceptibility to apoptogenic insults (47, 48), the molecular basis of the latter phenomenon remains to be fully defined. We have tested the hypothesis that the inability of cisplatin to down-regulate IAP may be an important contributing factor for chemoresistance in human ovarian cancer. We hereby report that 1) cisplatin failed to alter Xiap and Hiap-2 contents or induce apoptosis in the cisplatin-resistant cells; 2) overexpression of Xiap by adenoviral sense cDNA infection is effective in attenuating cisplatin-induced apoptosis in chemosensitive cells; and 3) Xiap antisense expression decreased C13 cell viability. These findings suggest that down-regulation of Xiap may increase the sensitivity of the chemoresistant cells to cisplatin and may be a potential strategy for gene therapy for cisplatin-resistant ovarian cancer. In this context, we have recently observed that down-regulation of Xiap by adenoviral antisense expression not only induced apoptosis in chemoresistant hOSE cancer cells (C13) in vitro, but also sensitized the cells to the cytotoxic action of cisplatin (29).
In summary, our findings suggest that Xiap may be a target for chemotherapeutic agents in the induction of apoptosis, and that the ability of cisplatin to down-regulate IAP may be an important factor in chemosensitivity. These studies provide important insight on the involvement of IAPs in the regulation of apoptosis in ovarian cancer cells, the mechanisms of action of chemotherapeutic agents, and the molecular basis of chemoresistance.
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Acknowledgments |
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Footnotes |
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2 Recipient of a Cancer Research Society Postdoctoral Fellowship.
3 Recipient of a Corinne Boyer Fund for Ovarian Cancer Research
Postdoctoral Fellowship.
4 Recipient of a Natural Science and Engineering Research Council of
Canada Graduate Scholarship.
Received August 9, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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in hen granulosa cells during ovarian follicular
development. Biol Reprod 52:1050–1058[Abstract]
inhibits apoptosis in hen granulosa cells. Proceedings of
the 11th Ovarian Workshop: Ovarian Cell Growth Apoptosis and Cancer,
London, Canada, 1996, p 17
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 G. K. Yiu, W. Y. Chan, S.-W. Ng, P. S. Chan, K. K. Cheung, R. S. Berkowitz, and S. C. Mok SPARC (Secreted Protein Acidic and Rich in Cysteine) Induces Apoptosis in Ovarian Cancer Cells Am. J. Pathol., August 1, 2001; 159(2): 609 - 622. [Abstract] [Full Text]
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