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Cell, Tumor and Stem Cell Biology |
1 Cancer Research UK Labs, Department of Cancer Medicine; 2 Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Hospital, London, United Kingdom; 3 Laboratory of Molecular Signalling, The Babraham Institute, Cambridge, United Kingdom; and 4 Department of Physiological Chemistry, Centre for Biomedical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands
Requests for reprints: Eric Lam, Cancer Research UK Labs, Department of Cancer Medicine, Imperial College London, Hammersmith Hospital, Medical Research Council Cyclotron Building, Du Cane Road, London W12 0NN, United Kingdom. Phone: 44-20-8383-5829; Fax: 44-20-8383-5830; E-mail: eric.lam{at}imperial.ac.uk.
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Abstract |
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Introduction |
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The FOXO class of forkhead proteins are downstream targets of the phosphatidylinositol-3-kinase (PI3K)/Akt pathway. Activated PI3K phosphorylates phosphatydylinositol (4, 5) diphosphate (PIP2) on the 3-position, thereby forming phosphatydylinositol (3–5) triphosphate (PIP3). PIP3 binds to the serine/threonine kinase Akt via its pleckstrin homology domain, which causes its translocation to the inner surface of the cell membrane. At the cell membrane, Akt becomes activated by phosphorylation, catalyzed by PDK1. FOXOs are phosphorylated by Akt on highly conserved serine and threonine residues, resulting in impaired DNA binding activity and increased binding to the chaperone protein, 14-3-3. Newly formed 14-3-3-FOXO complexes are then exported from the nucleus (reviewed in ref. 5), thereby inhibiting FOXO-dependent transcription of key target genes that promote cell cycle arrest and apoptosis, such as p27Kip1 and Bim (6–9).
We previously showed that paclitaxel treatment of breast cancer cells stimulates the expression of the FOXO family member FOXO3a, which in turn increases cell death by inducing the expression of the Bcl-2 homology 3 domain (BH3)-only proapoptotic protein Bim (6). Others have shown that overexpression of Akt can increase resistance to paclitaxel (10, 11), further emphasizing the importance of PI3K/Akt/FOXO pathway in determining drug sensitivity. Other signal transduction pathways may also affect paclitaxel sensitivity. For instance, the mitogen-activated protein kinases (MAPK) extracellular signal-regulated kinase 1/2 (ERK1/2) become activated following paclitaxel treatment (12), and enhanced paclitaxel-induced cellular toxicity has also been observed following ERK1/2 inhibition (13). Similarly, p38 MAPK, a member of the stress response class of MAPKs, is also activated following paclitaxel treatment, and inhibition of this kinase also augments the apoptotic response (14).
Whereas the available evidence suggests that activation of the PI3K, ERK1/2, and p38 pathways may protect cells from the toxic effects of paclitaxel, the reverse seems to be true for members of the JNK family. JNK1 and JNK2 belong to the MAPK family and phosphorylate components of the activator protein transcription factor complex, such as c-Jun and ATF2, as well as TCF/ELK (15–17). In the same way that MAPK is activated by a series of sequential phosphorylation events by MAPKK, JNK is also activated by JNK kinase/SEK1/MAPKK through targeted phosphorylation of conserved threonine and serine residues (18). JNK kinase is in turn activated following phosphorylation by either MAPK kinase kinase 1 or 3 (MEKK1 or MEKK3), as well as by apoptosis signal-regulating kinase-1 (19). Many forms of cellular insult lead to activation of JNK, including UV light, osmotic stress, and irradiation (20–22). JNK signaling is activated following paclitaxel treatment (23–25), but unlike Akt, ERK1/2, and p38, inhibition of JNK reduces apoptosis following paclitaxel treatment (24).
We have previously reported that silencing of FOXO3a by small interfering RNA greatly reduces the induction of apoptosis caused by paclitaxel (6). The observations by others that JNK signaling is also needed for paclitaxel-induced apoptosis suggest a possible crosstalk between the PI3K-Akt-FOXO3a and JNK signaling pathways. In this report, we show that paclitaxel not only induces FOXO3a expression but also enhances its nuclear relocation through JNK-dependent inhibition of the PI3K/Akt signaling pathway.
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Materials and Methods |
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MEKK3:ER*; ref. 27) were maintained in DMEM supplemented with 10% fetal bovine serum, 2 mmol/L glutamine, and 100 units/mL of penicillin/streptomycin in a humidified incubator in an atmosphere of 10% CO2 at 37°C. Paclitaxel was obtained from Sigma Chemical Co. (Poole, United Kingdom), and SP600125, SB203580, and PD98059 were from Tocris (Avonmouth, United Kingdom); LY294002 and Triciribine were from Calbiochem (via VWR International Ltd., Lutterworth, United Kingdom); all were dissolved in DMSO. Cell cycle analysis. Cell cycle analysis was done using propidium iodide staining as described (28). Briefly, cells were trypsinized, washed in PBS, and then fixed in 90% ethanol. Fixed cells were then washed twice in PBS and stained in 50 µmol/L propidium iodide containing 5 µg/mL Dnase-free RNase (Sigma, Poole, United Kingdom) for 1 hour, then analyzed by flow cytometry using a FACSCalibur (Becton Dickinson, Cowely, United Kingdom) and analyzed using Cell Quest software (Becton Dickinson).
Western blotting. Western blotting was done on whole-cell extracts prepared by lysing cells in NP40 lysis buffer [1% NP40, 100 mmol/L NaCl, 20 mmol/L Tris-HCl (pH 7.4), 10 mmol/L NaF, 1 mmol/L sodium orthovanadate, 30 mmol/L Naß-glycerophosphate, and protease inhibitors ["Complete" protease inhibitor cocktail, as instructed by the manufacturer (Roche, Welyn Garden City, United Kingdom)] on ice for 15 minutes. Insoluble material was removed by centrifugation, and protein concentration was determined by Bio-Rad Dc protein assay (Bio-Rad, Hemel Hempstead, United Kingdom). Twenty micrograms of protein were size fractionated using SDS-PAGE and electrotransferred onto Protran nitrocellulose membranes (Schliecher and Schuell, Dassel, Germany). Membranes were incubated with specific antibodies recognizing FOXO3a phosphorylated at Thr32 (06-953, Upstate, Dundee, United Kingdom), total FOXO3a (06-951, Upstate). Antibodies specific for Akt phosphorylated at the Ser473 (9271), Akt (9272), JNK1/2 phosphorylated at Thr183/Tyr185 (9251), JNK1/29 (9252), c-Jun phosphorylated at Ser73 (9164), p38 phosphorylated at Thr180/Tyr182 (9211), p38 (9212), ERK1/2 phosphorylated at Thr202/204 (9101), total Erk1/2 (9102), and human caspase-9 (9502) were purchased from Cell Signaling Technologies (Hitchin, United Kingdom). Antibody to c-Jun (H79) was purchased from Santa Cruz (La Jolla, CA). Primary antibodies were detected using horseradish peroxidase–linked anti-mouse or anti-rabbit conjugates as appropriate (DAKO, Ely, United Kingdom) and visualized using the enhanced chemiluminescence detection system (Amersham Biosciences, Amersham, United Kingdom). Nuclear and cytoplasmic lystes were prepared according to ref. (29). Briefly, cells were lysed on ice for 20 minutes in buffer containing 10 mmol/L HEPES (pH 7.4), 10 mmol/l KCl, 0.01 mmol/L EDTA, 0.1 mmol/L EGTA, 2 mmol/L DTT, 10 mmol/L NaF, 1 mmol/L sodium orthovanadate, 30 mmol/L Naß-glycerophosphate, and protease inhibitors ("Complete" protease inhibitor cocktail, as instructed by the manufacturer; Roche). Nuclei were sedimented by centrifugation, and the supernatant (cytoplasmic fraction) was retained. Nuclei were lysed in the same buffer containing 1% v/v NP40 and 400 mmol/L NaCl.
Immunofluorescence. Cells were grown on sterile, 13-mm-diameter coverslips and fixed in 4% formaldehyde before being permeabilized in 0.01% v/v Triton X-100. Coverslips were blocked in PBS containing 3% bovine serum albumin, and antibody recognizing FOXO3a or Bim (N20 Santa Cruz, La Jolla, USA) was added at 80 µg/mL. Specific staining was visualized with a secondary antibody conjugated to Alexa 488 (antirabbit) or Alexa 647 (antigoat; Molecular Probes, Eugene, OR) and analyzed on a Zeiss confocal microscope with LSM meta 510 software.
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Results |
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Activation of JNK requires dual phosphorylation of conserved Thr183 and Tyr185 residues that can be monitored using phospho-specific antibodies. Upon paclitaxel treatment, the levels of phospho-JNK1/2 increased, which was first apparent as early as 4 hours after treatment, and this was followed by an increase in total JNK1/2 levels. The levels of activated p38 but not total p38 increased 16 hours after paclitaxel treatment and remained elevated throughout the time course. A similar profile, albeit less pronounced, was found for activated (phosphorylated at residues Thr202 and Tyr204) and total ERK1/2. The Western blot results also showed that the expression of the FOXO3a target Bim increased from 24 hours after paclitaxel treatment and remained high. Active caspase-9 levels also increased, reaching a maxima at 48 and 72 hours after treatment, indicating that apoptosis was occurring in these cells at these times.
Activation of the JNK1/2 but not the ERK1/2 or p38 signaling pathways is required for the induction of apoptosis in paclitaxel-treated MCF-7 cells. To determine which of the kinases activated by paclitaxel affects breast cancer cell survival, we treated MCF-7 cells with SP600125, SB203580, and PD98059, which are inhibitors of JNK1/2, p38, and MAP/ERK kinase 1 (MEK1; the upstream activator of ERK1/2), respectively. Cells were analyzed by flow cytometry, and the extent of apoptosis was determined by measuring the fraction of cells with sub-G1 DNA content. As shown in Fig. 2A, untreated MCF-7 cells displayed negligible apoptosis, and cells remained in exponential growth throughout the time course. Paclitaxel induced apoptosis of MCF-7 cells, and the levels gradually increased over the 72-hour treatment period. Cells also arrested in the G2-M phase of the cell cycle upon paclitaxel treatment, in agreement with previous reports (3, 6). Treatment of MCF-7 cells with the JNK inhibitor SP600125 alone also caused accumulation of cells in the G2-M phase of the cell cycle, but the fraction of cells undergoing apoptosis was far lower when compared with paclitaxel-treated cells. However, when cells were treated with a combination of SP600125 and paclitaxel, the cell cycle phase distribution profiles resembled those of cells treated with SP600125 alone. Interestingly, the percentage of cells undergoing apoptosis was dramatically lower than those with paclitaxel alone, indicating that inhibition of JNK1/2 activation protects against the cytotoxic effects of paclitaxel. Treatment of cells with the MEK1 inhibitor PD98059 or p38 inhibitor SB203580 alone did not elicit a cell death response at any time point or induce discernable changes in the cell cycle phase distributions. Furthermore, PD98059 as well as SB203580 failed to protect the cells against paclitaxel-induced apoptosis. Together, these results show that the activation of JNK but not ERK or p38 is necessary for the induction of apoptosis in response to paclitaxel treatment.
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JNK signaling is required for FOXO3a activation in response to paclitaxel. Next, we investigated the consequences of JNK1/2 inhibition on the signaling intermediates activated by paclitaxel. As shown in Fig. 3, SP600125 markedly attenuated the drop in phospho-FOXO3a levels upon 16 hours of treatment with paclitaxel, this reduction was not observed in cells treated with a combination of SP600125 and paclitaxel. Treatment with SP600125 alone slightly lowered the phospho-FOXO3a levels but much less so than paclitaxel. There was little variation in total FOXO3a levels, regardless the treatment within the time course. The phosphorylation status of Akt mirrored that of FOXO3a, and SP600125 largely abolished the decline in phospho-Akt levels upon paclitaxel treatment. Furthermore, treatment with SP600125 alone modestly inhibited Akt phosphorylation. The activation of JNK1/2 (phospho-JNK1/2) and the downstream target (phospho-c-Jun) upon paclitaxel treatment was abolished in the presence of SP600125. Interestingly, we observed a consistent, albeit very modest, increase in c-Jun levels in the paclitaxel but not paclitaxel plus SP600125-treated cells. This has been reported previously and may reflect stabilization of c-Jun by JNK1/2-dependent phosphorylation (26). The activation of ERK1/2 and p38 by phosphorylation seemed unaffected by inhibition of JNK1/2, suggesting that SP600125 does not affect the activity of these signaling molecules.
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MEKK3:ER* (27). MEKK3:ER* consists of the isolated kinase domain of MEKK3 fused in frame to the hormone-binding domain of the human estrogen receptor. Treatment of RM3 cells with 4-hydroxytamoxifen causes dissociation of hsp90 and rapid activation of the kinase domain. Treatment with 4-hydroxytamoxifen increased the levels of phospho-JNK1/2 in RM3 cells but not in the parental Rat1 cells (Fig. 5A). JNK activation coincided with decreased levels of phospho-Akt and phospho-FOXO3a. JNK activation coincided with decreased levels of phospho-Akt and phospho-FOXO3a. However, tamoxifen treatment of RM3 cells also activated p38 and ERK1/2. To confirm that the reduced levels of phospho-Akt and phospho-FOXO3a observed in 4-hydroxytamoxifen–stimulated RM3 cells were the result of JNK1/2 activation and not a consequence of combined activation of JNK1/2, p38, and ERK1/2, the experiments were repeated in the presence of SP600125, SB203580, or PD98059. As shown in Fig. 5B, the JNK1/2 inhibitor SP600125 completely abolished the decline in phospho-FOXO3a upon tamoxifen treatment of RM3 cells. In contrast, inhibition of MEK1 or p38 signaling had no effect on the phosphorylation status of FOXO3a, indicating that conditional activation of JNK1/2 is sufficient to antagonize Akt activity and attenuate FOXO3a phosphorylation.
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Discussion |
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MEKK3:ER*, an upstream activator of the JNK1/2 pathway, resulted in inhibition of Akt and FOXO3a phosphorylation. Furthermore, fibroblasts null for both the Jnk1/Jnk2 loci contained less nuclear FOXO3a than wild-type controls and also exhibited higher levels of phosphorylated FOXO3a. Taken together, these results suggest that the main determinant of FOXO3a subcellular distribution is the PI3K-Akt signaling pathway, and this pathway may be subject to regulation by JNK1/2. This is the first report detailing the ability of JNK1/2 to regulate both Akt activity and thus the nuclear localization of FOXO3a in mammalian cells. Furthermore, the observation that inhibition of JNK1/2 protected a panel of breast cancer cell lines from paclitaxel-induced apoptosis combined with the fact that paclitaxel failed to repress both Akt and FOXO3a phosphorylation and FOXO3a nuclear translocation in JNK1/2 null MEFs suggests that this mechanism is widespread. The data shown here clearly shows that treatment of MCF-7 cells with paclitaxel resulted in an initial transient stimulation of Akt followed by an immediate inhibition, which has been observed in other cell types (10). Indeed, the inhibition of Akt activity seems necessary for the induction of paclitaxel-induced apoptosis, because there are a number of reports that show that either enhanced activation of endogenous Akt or ectopic expression of a constitutively active Akt protects cells against the cytotoxic effects of paclitaxel (10, 11, 30, 31). Indeed, we have also observed that MCF-7 cells expressing a dominant-negative Akt expression construct undergo apoptosis more readily than control cells.5 One explanation for this is that the inhibition of Akt would directly affect the phosphorylation status of FOXO3a, thereby resulting in its nuclear translocation and subsequent activation of target genes, which is in agreement with our previous observations (6).
Following the treatment of MCF-7 cells with paclitaxel, we observed an induction of JNK activity as measured by the increased levels of phospho-JNK1/2 and the JNK substrate phospho-c-Jun. The initial increase in phospho-JNK1/2 paralleled that of Akt, but unlike phospho-Akt, this increase was prolonged. Our observations that JNK1/2 activity was elevated and prolonged in both MCF-7 and in MEFs coupled with the observation that inhibition by SP600125 suggests that the activation of JNK1/2 is required for paclitaxel-induced apoptosis. The activation of JNK1/2 and the inactivation of Akt following paclitaxel treatment suggested that there maybe crosstalk between these two signal transduction pathways. Indeed, our results indicated that activation of JNK in a 4-hydroxytamoxifen–inducible MEKK3-expressing cell line resulted in the reduction of Akt activity, as did our observation that MEF cells derived from JNK null mice contained higher levels of active Akt. Although the mechanism of this postulated inhibition of Akt by JNK1/2 is unclear, there is evidence that JNK is able to block insulin signaling via IRS phosphorylation (32).
With respect to the data shown here in which inhibition of JNK1/2 signaling prevented the nuclear localization of FOXO3a and protected cells from paclitaxel induced apoptosis, there are examples of JNK signaling affecting FOXO family members. Recent data has shown that JNK signaling can extend life span in Drosophila using a mechanism that represses insulin signaling and requires Drosophila FOXO (33). Furthermore, in Caenorhabditis elegans, it has been shown that the homologue of mammalian FOXO family members, DAF-16, is responsible for longevity and is regulated by insulin (34). It has also been shown that DAF-16 is directly phosphorylated by C. elegans JNK following heat shock, thereby increasing stress resistance and longevity via a mechanism that involves nuclear translocation of DAF-16 (35). In MEFs, it has been shown that the small GTPase RAL stimulates JNK activity, and that JNK1/2 phosphorylate FOXO4 directly at Thr447 and Thr451, thereby enhancing FOXO4 activity (36). Although we have no direct evidence that JNK1/2 phosphorylate FOXO3a, we have observed a slower migrating form of FOXO3a in Western blots that is absent in the presence of SP600125. Whether this is a direct or indirect phosphorylation induced by JNK or a secondary modification caused indirectly by JNK1/2 is as yet unknown and will form the basis of further investigation.
The nuclear localization of FOXO3a is a prerequisite for transcriptional transactivation and, accordingly, the majority of FOXO3a was located in the cytoplasm in exponentially growing MCF-7 cells. However, this was not the case in either JNK1/2 null or control fibroblasts. In both these cases, the cells remained healthy, despite the apparent high levels of FOXO3a found in the nucleus of the mouse fibroblasts. This observation would suggest that there is a threshold for the amount of FOXO3a present in the nucleus that is required to induce cell cycle arrest and apoptosis (34, 37, 38). An attractive explanation would be that the apoptosis induced by paclitaxel is in part mediated by increased nuclear translocation of FOXO3a to a level at which exceeds this threshold, thereby allowing transcription of FOXO target genes. However, it is likely that there are other factors, which potentiate the activity of FOXOs once they are within the nucleus, such as direct phosphorylation by JNK1/2 (36) and other kinases. Thus, FOXO3a may be regulated by JNK on two levels, one whereby stress-induced JNK1/2 activity results in Akt inhibition and nuclear translocation as seen here, coupled with direct phosphorylation activity, which modulates the transcriptional activity as previously reported (36). This would also help to explain the continued survival of the control and JNK1/2 null MEFs, which had high levels of nuclear FOXO3a, which may not be fully active.
In summary, we have shown through the use of conditional protein kinases, selective protein kinase inhibitors, and JNK1/2 double null fibroblasts that JNK1/2 signaling plays a key role in determining the extent of apoptosis in response to paclitaxel. This may be in large part due to the JNK-dependent dephosphorylation, nuclear accumulation, and activation of FOXO3a. This suggests that patients with high levels of functional FOXO3a and JNK1/2 may respond more favorably to paclitaxel regimens. It is also possible that coadministration of agents that activate JNK may synergize with paclitaxel to promote tumor cell death, and that JNK activation may be a therapeutically desirable end point. This study is the first demonstration that JNK1/2 signaling regulates FOXO3a function and, in turn, the sensitivity of breast cancer cell lines to paclitaxel. This indicates that FOXO3a and JNK1/2 may be important targets in breast cancer and in the prediction of drug sensitivity.
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Acknowledgments |
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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Footnotes |
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S. Cook is a Senior Cancer Research Fellow of Cancer Research UK.
5 A. Sunters and E.W.-F. Lam, unpublished observations. 
Received 6/ 8/05. Revised 9/16/05. Accepted 10/10/05.
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MEKK3:ER* activation induces a p38 
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