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Reproductive Biology Unit and Division of Gynaecological Oncology, Departments of Obstetrics and Gynaecology and Cellular and Molecular Medicine, University of Ottawa, Ottawa Health Research Institute, The Ottawa Hospital (Civic Campus), Ottawa, KIY 4E9 Canada [M. F., B. M. L., X. Y., B. K. T.], and Department of Pathology, University of South Florida College of Medicine and H. Lee Moffitt Cancer Center, Tampa, Florida 33612 [H. C. D., J. Q. C.]
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ABSTRACT |
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-hydrobromide (30 µM) but restored by exogenous wild-type p53. CDDP increased p53, decreased Xiap content, and induced apoptosis in OV2008 cells but not in the resistant counterpart (C13*). However, dominant-negative Akt restored all of these characteristics to C13* cells. Expression of a constitutively active Akt2 prevented CDDP-mediated down-regulation of Xiap and apoptosis in A2780s cells. Akt2-mediated chemoresistance could not be reversed by Xiap down-regulation. These results suggest that whereas Xiap, Akt2, and p53 are important mediators of chemoresistance in ovarian cancer cells, Akt2 may be an important regulator of both Xiap and p53 contents after CDDP challenge. Inhibition of Xiap and/or Akt expression/function may be an effective means of overcoming chemoresistance in ovarian cancer cells expressing either endogenous or reconstituted wild-type p53. |
Introduction |
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TopABSTRACTIntroductionMaterials and MethodsResults and DiscussionREFERENCES |
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The inhibitors of apoptosis proteins, originally identified in baculovirus, are potent endogenous inhibitors of programmed cell death. Xiap is an inhibitor of the execution caspase-3 and -7 and directly suppresses the mitochondrial apoptotic pathway by inhibiting caspase-9 (3) . Our laboratory has demonstrated previously that CDDP decreases Xiap protein level, induces Akt cleavage, and induces apoptosis in chemosensitive, p53 wild-type ovarian epithelial cancer cells (4) . These responses were not observed in chemoresistant, p53 wild-type ovarian epithelial cancer cells (C13*). However, down-regulation of Xiap by adenoviral antisense in C13* cells increased CDDP sensitivity (5) . By contrast, Xiap down-regulation was unable to induce apoptosis or increase CDDP sensitivity in CDDP-resistant, mutant p53 ovarian cancer cells (A2780cp), suggesting that p53 status is a determinant of Xiap-mediated chemoresistance. Taken together, these results suggest that Xiap regulates chemosensitivity by protecting cells from CDDP-induced apoptosis and that Xiap may manifest some of its effects through modulation of a p53-mediated pathway. In addition, Xiap overexpression induces chemoresistance and Akt phosphorylation, indicative of Akt activation, effects that were attenuated by the PI3K inhibitor LY294002 (6) . Together, these data suggest that Xiap-mediated chemoresistance may be caused in part by the activation of the PI3K/Akt pathway. It has been shown in a number of cell types that Akt1 (Akt), Akt2, and Akt3 promote cell survival and suppress apoptosis induced by a variety of stimuli. A major downstream target of these kinases is Bad, a proapoptotic member of the Bcl-2 family of apoptotic regulators (7, 8, 9, 10) . The enzymes also phosphorylate and inactivate members (FKHR/FKHRL1) of the Forkhead transcription factor family (11 , 12) , which are involved in the regulation of FasL transcription. Studies have demonstrated alterations of Akt2 at the DNA or mRNA levels in 15–20% of human ovarian cancers as well as Akt2 activation and overexpression in primary ovarian carcinomas (1 , 13) . However, the relationship among Akt2, Xiap, and other mediators of chemoresistance is unknown.
In the current study, we demonstrate that both Xiap and Akt2 can modulate CDDP sensitivity but that Akt2 is involved in regulating Xiap content in the presence of CDDP. Furthermore, we demonstrate that functional p53 is absolutely required for the chemosensitizing effects of Xiap and/or Akt down-regulation. Overall, our results are consistent with the notion that modulation of Xiap or Akt function may be a useful therapeutic strategy in overcoming chemoresistance in tumors expressing wild-type p53 or in tumors supplemented with exogenous p53.
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Materials and Methods |
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TopABSTRACTIntroductionMaterials and MethodsResults and DiscussionREFERENCES |
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Cell Culture.
CDDP-sensitive (OV2008 and A2780s) and -resistant (C13* and A2780cp) cell lines were cultured as reported previously (6)
. Before each experiment, 1.8 x 105 cells were plated on uncoated 6-well plates in the appropriate medium with 10% fetal bovine serum for 12–18 h for proper attachment.
Creation of Stably Transfected Cell Lines.
A2780s cells were stably transfected with pcDNA3 vector (Invitrogen) containing constitutively active HA-tagged, myristoylated Akt2 or pcDNA3 alone as reported previously in Yuan et al. (14)
.
Adenovirus Infection and CDDP Treatment.
After 12–18 h of plating, cells were infected with adenoviral Xiap-s, Xiap-as, wild-type p53, DN-Akt, and/or LacZ control at various viral doses (MOI) as reported previously (6)
. Total MOI was maintained constant for all treatment groups. Adenovirus infection efficiency (MOI = 5; 24 h) was >90%, as determined by a 5-bromo-4-chloro-3-indolyl-ß-D-galactopyranoside-staining assay against LacZ construct-infected cells. Unless otherwise specified, 10 µM CDDP was dissolved in DMSO and added to the cells in culture medium with 2% fetal bovine serum at 24 h before harvest.
Determination of Apoptosis.
After treatment, cells were harvested as described in Asselin et al. (6)
, and the percentage of apoptosis was determined by nuclear staining with Hoechst 33248 stain (12.5 ng/ml; Sigma), as reported in Sasaki et al. (5)
.
Protein Extraction and Western Immunoblotting.
Cells were sonicated in lysis buffer containing 50 mM HEPES, 150 mM NaCl, 1.5 mM MgCl2, 1 mM EGTA, 100 mM sodium fluoride, 10 mM Na PPi, 10% (v/v) glycerol, 1% (v/v) Triton X-100, 1 mM phenylmethylsulfonyl fluoride, 10 µg/µl aprotinin, and 1 mM Na3(VO4). Proteins were isolated and quantified according to previously published protocols (5)
. Equivalent amounts of total protein were loaded onto acrylamide gels (8–10%), separated by PAGE, and transferred to nitrocellulose membranes according to previously published protocols (5)
. Ponceau-S staining was used to confirm even loading between groups. The membranes were blocked for 1 h in Blotto (5% skim milk in Tris-buffered saline-Tween) and subsequently incubated for 12 h at 4°C in primary antibodies diluted in Blotto (anti-Xiap, 1:2000; anti-p53, 1:1000; anti-p21, 1:2000; anti-HA, 1:1000). For the detection of primary antibodies, membranes were incubated with horseradish peroxidase-conjugated goat IgG raised against the proper species (goat antirabbit for anti-Xiap and goat antimouse for anti-HA, anti-p53, anti-p21; Bio-Rad) diluted 1:2000 in Blotto for 1 h at room temperature. Horseradish peroxidase activity was visualized using an enhanced chemiluminescence detection kit (Amersham Pharmacia Biotech), and the signals were recorded on HyperFilm MP (Amersham Pharmacia Biotech) and developed in a Kodak X-Omat film developer. Results were scanned and densitometrically analyzed using Scion Image software (Scion Inc).
Statistical Analysis.
Experimental results are expressed as the mean of at least three-independent experiments. Data were analyzed using one- or two-way ANOVA with Tukey post-test or two-tailed t tests to assess differences between experimental groups (PRISM 3.0; GraphPad Software, Inc.). Statistical significance was inferred at P < 0.05.
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Results and Discussion |
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TopABSTRACTIntroductionMaterials and MethodsResults and DiscussionREFERENCES |
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). To further assess the role of Xiap in chemoresistant cells, C13* cells were infected with adenovirus carrying Xiap-as cDNA at various MOIs (MOI = 0, 10, 20, 30, and 40) for a total of 48 h. At 24 h after infection, cells were treated with 10 µM CDDP or DMSO control. Western analysis confirmed down-regulation of Xiap by Xiap-as. Although down-regulation of Xiap alone did not induce apoptosis, sensitivity toward CDDP increased significantly as a function of Xiap-as MOI (P < 0.05; Fig. 1B
). These results confirm the involvement of Xiap in chemoresistance, as reported previously by our laboratory (4, 5, 6)
.
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and OV2008 cells (Fig. 2B)
when infected with LacZ (MOI = 45). Xiap-s induced resistance toward CDDP compared with LacZ control in both A2780s (P < 0.01) and OV2008 (P < 0.05) cells. In the absence of CDDP, replacement of LacZ with DN-Akt in A2780s cells induced apoptosis in a dose-dependent manner (MOI = 0, 10, 20, and 40) despite the presence of Xiap-s (MOI = 5; data not shown). However, no significant change in apoptotic response was observed in OV2008 under the same conditions, suggesting that the A2780s cell line is more dependent on the integrity of Akt for its survival than the OV2008 cell line. However, in both A2780s and OV2008 cells, replacement of LacZ with DN-Akt attenuated the protective effect of Xiap. CDDP-induced apoptotic response was restored up to 70% of control (LacZ; MOI = 45) in cells coexpressing Xiap (MOI = 5) and DN-Akt (MOI = 40). Taken together, these results support our hypothesis that Xiap is a determinant of CDDP sensitivity in ovarian cancer cells and that Akt is a downstream intermediate of Xiap-mediated chemoresistance.
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is resistant to paclitaxel, relative to the parental control cells, an effect that was reversed by the PI3K inhibitor LY294002 (16)
. Moreover, data from our own laboratory have demonstrated that Xiap-mediated chemoresistance is partially attenuated by LY294002 (6)
. In addition, a recent time course study has demonstrated that expression of an active Akt2 in ovarian cancer cells renders the cells resistant to CDDP (14)
. In investigating further the mechanisms of Akt-mediated chemoresistance, we have extended these observations with a concentration-response study using chemosensitive ovarian cancer cells (A2780s), stably transfected with pcDNA3 expression vector carrying constitutively active Akt2 (A2780s-AAkt2). Responses to CDDP (0, 2.5, 5, 10, and 20 µM) were compared with A2780s cells stably transfected with empty pcDNA3 vector (A2780s-PMH6). Although CDDP induced apoptosis in a concentration-dependent manner in A2780s-PMH6 cells (P < 0.01), the presence of constitutively activated Akt2 reduced the sensitivity of cells toward CDDP (P < 0.01; Fig. 3A
). These data are consistent with results demonstrated by Yuan et al. (14)
.
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). Taken together, these data confirm that Akt modulates the sensitivity of human ovarian cancer cells to CDDP.
p53 Function Is Required for Sensitization to CDDP Through Suppression of Akt Activity.
Previous studies from our laboratory have established that Xiap down-regulation sensitizes chemoresistant, p53 wild-type (C13*) but not p53 mutant (A2780cp) ovarian cancer cells to CDDP (5)
. However, concomitant reintroduction of wild-type p53 induced apoptosis and permitted the CDDP-sensitizing effects of Xiap down-regulation in these p53 mutant cells. To determine whether p53 was also required for the chemosensitizing effects of Akt activity down-regulation, A2780cp cells were infected with DN-Akt (MOI = 0, 10, 20, and 40) for 48 h, followed by subsequent treatment with 10 µM CDDP for 24 h. DN-Akt failed to sensitize A2780cp cells to CDDP (data not shown), suggesting that a wild-type p53 is required for the proapoptotic effects of down-regulation of Akt activity. To determine whether p53 status is indeed a determinant of Akt-mediated chemoresistance, A2780cp cells were coinfected with DN-Akt (MOI = 0, 10, 20, and 40) and wild-type p53 (MOI = 10). The presence of reconstituted wild-type p53 sensitized the cells to CDDP in a DN-Akt-dependent manner (P < 0.001, CDDP; P < 0.01, DN-Akt; P < 0.05, interaction; Fig. 4A
). This effect was also dependent on the concentration of wild-type p53 when the DN-Akt dose was held constant (P < 0.0001, all effects; Fig. 4B
). The combined results demonstrate that although suppression of Akt sensitizes chemoresistant cells to CDDP, this effect requires the presence of a wild-type p53.
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). Interestingly, at 40 µM, PFT increased overall cell death in all groups, indicative of nonspecific PFT toxicity; we subsequently determined the maximum tolerable dose of PFT to be 30 µM (data not shown), and this concentration was used for all subsequent experiments.
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). Although DN-Akt failed to sensitize these cells to CDDP, introduction of wild-type p53 dose-dependently sensitized the cells to CDDP (P < 0.0001). Addition of PFT significantly attenuated apo-ptosis overall (P < 0.01) and significantly ablated the effects of wild-type p53 (P < 0.05). To confirm the functionality of the exogenous wild-type p53, we determined p21 content. Although p21 content was undetectable in the absence of exogenous p53, reintroduction of wild-type p53 increased p21 content in a dose-dependent manner, an effect that was attenuated by the presence of PFT (Fig. 5B)
.
To confirm that the actions of PFT were, at least in part, specific to p53, C13* cells were infected with DN-Akt (MOI = 0, 40, and 80) and wild-type p53 (MOI = 0, 5, 10, and 20) and treated with 10 µM CDDP in the presence and absence of PFT (30 µM). Although expression of DN-Akt sensitized the cells to CDDP in a dose-dependent manner (P < 0.0001), this effect was attenuated by pretreatment with PFT (P < 0.01). However, the effects of PFT were reversed by overexpression of wild-type p53 (P < 0.0001), suggesting that the effects of PFT are, at least in part, mediated through p53 (Fig. 5C)
. Finally, there was a significant interaction between DN-Akt and wild-type p53 (P < 0.05), suggesting that Akt down-regulation is more effective at sensitizing the cells to CDDP when p53 content is high.
Thus, wild-type p53 function is required for the proapoptotic effects of either Xiap down-regulation (5) or Akt suppression; these effects are inhibited by pharmacological inhibitors of p53 or by endogenous mutant p53 and stimulated by the introduction of wild-type p53. As such, modulation of Xiap and/or Akt function may be a viable option in overcoming chemoresistance in tumors expressing wild-type p53. One recent review has suggested that there is an approximately 51% overall incidence of p53 mutation in epithelial ovarian cancer (20) . However, in tumors that express mutant p53, modulation of Xiap and/or Akt could conceivably be coupled to replacement of functional p53 by gene therapy, a process that was viable in at least one recent study (21) .
Akt Regulates the CDDP-Mediated Induction of p53.
The relative contribution of the p53 pathway to the modulation of chemosensitivity by Akt is not known. To test the relationship between Akt and p53, we cultured OV2008 and C13* cells with increasing doses of CDDP (0, 2.5, 5, and 10 µM). Although CDDP induced a concentration-dependent increase in p53 in the chemosensitive OV2008 cell line, p53 was not detectable in C13* cells at any of the CDDP doses (P < 0.00001, cell line; P < 0.01, CDDP; P < 0.01, interaction; Fig. 6A
).
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). Our finding that Akt regulates p53 content is consistent with the reports of Ogawara et al. (22)
, in which basal p53 levels could be controlled by Akt activation through activation, but not nuclear translocation, of MDM2. Similarly, we observed that the subcellular localization of MDM2 was Akt independent (data not shown). Whereas CDDP has previously been shown to increase p53 content (23)
, to our knowledge, our report represents the first to demonstrate that this process is negatively regulated by Akt. We are currently investigating the precise mechanisms by which Akt regulates the CDDP-mediated induction of p53.
Akt2 Protects Against CDDP-Induced Down-Regulation of Xiap.
Previous studies from our laboratory have demonstrated that CDDP decreases Xiap content in chemosensitive, but not chemoresistant, human ovarian cancer cells (4)
. However, if and how Akt is implicated in this process are not known. In accordance with our earlier data (4)
, CDDP (0–10 µM) decreased Xiap content in a concentration-dependent manner in OV2008 cells but not in C13* cells (P < 0.05, all effects; Fig. 6A
). This difference was most evident at 10 µM CDDP, in which OV2008 cells expressed only about 50% of basal (control) Xiap, compared with C13* cells, which showed no difference from the control cells (P < 0.001). However, when C13* cells were infected with DN-Akt (MOI = 0–80) and treated with 10 µM CDDP, Xiap was down-regulated in a DN-Akt-dependent manner (P < 0.01; Fig. 6B
).
As mentioned, Akt2 has been demonstrated to modulate cellular CDDP sensitivity in ovarian cancer cells (14)
. To examine whether Akt2 could regulate Xiap content, we used the A2780s-AAkt2 (active Akt2) and A2780s-PMH6 (control) cell lines. Although CDDP (10 µM) induced significant apoptosis (P < 0.001, relative to control; Fig. 6E
) and decreased Xiap content (60% decrease at 10 µM, P < 0.05 overall, relative to control; Fig. 6, C and E
) in A2780s-PMH6 cells, it failed to elicit either effect in A2780s-AAkt2 cells (P < 0.0001 compared with A2780s-PMH6, all effects), suggesting a possible role for Akt2 in the protection of Xiap against CDDP-induced down-regulation.
To test whether this protection of Xiap plays a significant role in the antiapoptotic effects of Akt2 activation, we down-regulated Xiap using an Xiap-as (MOI = 0–40; 48-h infection) in A2780s-AAkt2 cells, followed by treatment with 10 µM CDDP (24 h). Although Western blot analysis confirmed the down-regulation of Xiap by Xiap-as, CDDP-induced apoptosis was minimal and not significantly different in the two treatment groups (data not shown), suggesting that maintenance of Xiap content is a functionally minor downstream event in the antiapoptotic effects of Akt2 activation.
Thus, Akt2 regulates the CDDP-mediated down-regulation of Xiap. Interestingly, it has been reported that Xiap is an in vitro substrate for cleavage by a number of caspases, including caspase-3, -6, -7, and -8 (24) . In the same study, it was reported that Fas-induced apoptosis was associated with cleavage of Xiap. Thus, it is possible that Xiap is cleaved by CDDP-dependent activation of caspases, an effect that is inhibited by Akt2. In such a case, the failure of CDDP to decrease Xiap content in chemoresistant cells may be secondary to aberrant regulation of the Akt2 pathway. Interestingly, Akt is known to phosphorylate and inactivate FKHRL1 and FKHR1 (11) , both key regulators of FasL expression. Our laboratory has demonstrated previously that CDDP can up-regulate both Fas and FasL in OV2008 and A2780s cells but can only up-regulate Fas in C13* cells and cannot up-regulate Fas and FasL in A2780cp cells, suggesting that deregulation of this system may be an important determinant of chemoresistance in ovarian cancer cells (25) . Whether activation of the Fas/FasL system by CDDP is an important event in the subsequent down-regulation of Xiap and whether this phenomenon is Akt2-dependent remain unclear.
Xiap is also known to act as its own E3 ubiquitin ligase (26) . It is possible, therefore, that aberrations in the ability of Xiap to become ubiquitinated and degraded in the 26S proteasome may underlie the observed maintenance of Xiap content in chemoresistant, but not chemosensitive, cells after CDDP challenge. Whether Akt2 modulates the process of Xiap ubiquitination is not known. However, it is clear that Akt2 is a central modulator of the cellular response to CDDP, both through its ability to inhibit the expression and function of proapoptotic proteins such as Bad and p53 and, interestingly, through its ability to protect antiapoptotic proteins such as Xiap from CDDP-induced down-regulation.
Note that Akt2 activation did not increase basal Xiap levels, as has been demonstrated in our laboratory in rat granulosa cells (27) . Moreover, down-regulation of Xiap did not attenuate Akt2-mediated chemoresistance. Thus, although Xiap is not required for the antiapoptotic effects of Akt2 activation, Akt2 is required for full implementation of Xiap-mediated chemoresistance. We are currently investigating the mechanism(s) by which Xiap is down-regulated in response to CDDP and by which Akt2 functions to inhibit this process.
In addition, our work provides evidence that reversal of chemoresistance can be achieved by inhibiting the function of either Xiap and/or Akt but that this process requires a functional p53 to be effective. It is likely, therefore, that suppression of Akt (or Xiap) sensitizes cells to p53-mediated apoptosis after CDDP challenge. Thus, in cells expressing mutant p53 or treated with PFT, Akt or Xiap, down-regulation has no effect on cell death because p53 is nonfunctional. In tumors expressing wild-type p53, suppression of Akt or Xiap could lead to reversal of chemoresistance. However, our data suggest that modulation of Akt activity may be a more effective mechanism of overcoming chemoresistance because Akt2 appears to control Xiap levels but can exert its antiapoptotic effects in the absence of Xiap.
Thus, our work has demonstrated that Akt is a key regulator of CDDP sensitivity, both through its ability to inhibit CDDP-induced apoptosis by itself and through its implication as a downstream intermediate of Xiap-mediated chemoresistance. Furthermore, we have shown that p53 is an important determinant of the response to Akt down-regulation in these cells, and we provide evidence that the increase in p53 content attributable to CDDP is negatively regulated by Akt. In addition, we show that Akt2 can regulate the effects of CDDP on Xiap content and that the failure of Xiap to be down-regulated by CDDP in chemoresistant cells is an Akt2-dependent phenomenon.
In conclusion, our work provides evidence that p53 is an important determinant of Akt-mediated chemoresistance and that Xiap and Akt are important, intimately related regulators of the cellular response to CDDP. Both p53 mutation and chemoresistance occur at extremely high frequencies in ovarian cancer. Our data suggest that overcoming chemoresistance by modulation of Xiap and/or Akt will, in some way, involve the restoration of p53 function in p53 mutant or null cells.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by a grant from the Canadian Institutes of Health Research (MOP-15691) and the National Cancer Institute of Canada (with funds from the Canadian Cancer Society, Grant 013335) to B. K. T. Supported by grants from the National Cancer Institute (CA77935 and CA89242) to J. Q. C. M. F. is the recipient of an Ontario Graduate Scholarship in Science and Technology. 
2 Both authors contributed equally to this work.
3 To whom requests for reprints should be addressed, at 725 Parkdale Avenue, Ottawa, Ontario, KIY 4E9 Canada. Phone: (613) 798-5555, ext. 16040; Fax: (613) 761-4403; E-mail: btsang{at}ohri.ca
4 The abbreviations used are: CDDP, cisplatin; PI3K, phosphatidylinositol 3'-kinase; Xiap, X-linked inhibitor of apoptosis protein; Xiap-as, Xiap antisense; Xiap-s, Xiap sense; FasL, Fas ligand; HA, hemagglutinin; MOI, multiplicity of infection; DN-Akt, dominant-negative Akt; PFT, pifithrin--hydrobromide.
Received 5/21/03. Revised 7/26/03. Accepted 8/20/03.
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REFERENCES |
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) or DMSO as CTL (
). Dose-dependent effects of DN-Akt (A) and wild-type p53 (B) on CDDP sensitivity were assessed. ***, P < 0.0001 relative to wild-type p53 (MOI = 0). +++, P < 0.0001 relative to CDDP-free group at same viral conditions. ++, P < 0.01 relative to CDDP-free group at same viral conditions.
