[Cancer Research 66, 6105-6110, June 15, 2006]
© 2006 American Association for Cancer Research
Molecular Biology, Pathobiology, and Genetics |
c-Jun NH2-Terminal Kinase/c-Jun Signaling Promotes Survival and Metastasis of B Lymphocytes Transformed by Theileria
Regina Lizundia1,
Marie Chaussepied1,
Michel Huerre2,
Dirk Werling4,
James P. Di Santo3 and
Gordon Langsley1
1 Institut Cochin, Département de Maladies Infectieuses, Faculté de Médecine René Descartes, Université Paris Descartes, INSERM U567, CNRS UMR 8104, 2 Unité de Recherche et d'Expertise Histotechnologie et Pathologie, Département de Pathogenèse Microbienne, 3 Unité des Cytokines et Développement Lymphoïde, INSERM U668, Département d'Immunologie, Institut Pasteur, Paris Cedex 15, France; and 4 The Royal Veterinary College, Hawkshead Lane, North Mymms, Hertfordshire, United Kingdom
Requests for reprints: Gordon Langsley, Institut Cochin, Département de Maladie Infectieuse, Paris, F-75014 France. Phone: 33-1-40-51-65-92; Fax: 11-33-1-40-51-65-70; E-mail: langsley{at}cochin.inserm.fr.
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Abstract
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Theileria parasites infect and transform bovine lymphocytes resulting in tumors with metastatic/invasive potential. Importantly, cellular transformation is reversed upon drug-induced parasite death, and the infected lymphocyte dies of apoptosis within 48 hours. Theileria-dependent transformation leads to the constitutive activation of c-Jun NH2-terminal kinase (both JNK1 and JNK2) and permanent induction of activator protein-1. Inactivation of JNK (following transfection of dominant-negative mutants, or treatment with a JNK-specific inhibitor) leads to lymphocyte apoptosis, suggesting an antiapoptotic role for JNK activation in Theileria-induced B cell transformation. Theileria-induced JNK activation also leads to constitutive c-Jun phosphorylation, and inhibition of c-Jun and activator protein-1 transactivation following the expression of a dominant-negative mutant of c-Jun sensitizes Theileria-transformed B cells to apoptosis, but does not significantly affect their proliferation. Thus, JNK activation and c-Jun induction have overlapping, but nonidentical antiapoptotic roles in Theileria-induced B cell transformation. Increased sensitivity to apoptosis may be related to the fact that the expression levels of antiapoptotic proteins such as Mcl-1 and c-IAP are reduced upon c-Jun inhibition. In addition, decreased c-Jun expression correlates with the impaired ability of transfected B cells to degrade synthetic matrix in vitro, and their injection into lymphoid mice gives rise to significantly less and smaller tumors. Combined, these data argue for a role for JNK and c-Jun induction in the survival and metastasis of Theileria-transformed B cells. The similarity between Theileria-transformed B cells with human B lymphomas argues that exploiting the reversible nature of Theileria-induced transformation could throw light on the mechanisms underlying human malignancies. (Cancer Res 2006; 66(12): 6105-10)
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Introduction
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The c-Jun NH2-terminal kinase (JNK) is a member of the mitogen-activated protein kinase family that is primarily stimulated by exposure to environmental stress and cytokines (1). JNK signaling pathway leads to NH2-terminal phosphorylation of c-Jun at residues Ser63 and Ser73 and increased transactivation of the activator protein-1 (AP-1) transcription factor. AP-1 is a mixture of dimers made up of members of the Jun family (c-Jun, JunB, and JunD), associated with proteins of the Fos (c-Fos, FosB, Fra1, and Fra2), and ATF2 families (2). Thus, the outcome of AP-1 activation results from combinatorial interactions between different family members, and the eventual end result is further complicated by the fact that not all family members have the same expression profiles. Furthermore, the plethora of potential readouts following JNK activation is extended due to the fact that there are three jnk genes that could be alternatively spliced to yield 10 different jnk isoforms (3). A number of studies, particularly in neuronal cells, show a proapoptotic role for JNK/c-Jun activation in apoptosis largely via transcriptional activation of proapoptotic genes such as Bim, although in contrast, JNK mediates an antiapoptotic signal that involves the transcription of Bcl2 in transformed B cells (1). Thus, depending on the cellular context, JNK/c-Jun stimulation could either reduce or promote cell survival. Cell migration and metastasis are also subjected to regulation by c-Jun and this occurs frequently in collaboration with members of the Fos family of dimerizing partners to regulate migration/metastasis as (defined as anchorage-independent growth), whereas its interaction with ATF-2 regulates growth factor–independent proliferation (4). Theileria parasites are unusual unicellular eukaryotes that infect bovine leukocytes and turn them into fully transformed cells (5). Exceptionally, the fully transformed state is reversed upon (drug-induced) parasite death and the host leukocyte dies of apoptosis if not further stimulated. One mechanism is due to the parasite permanently activating the nuclear factor 
B signaling pathway, probably through physical association with the IB-signalosome (6). Another mechanism is the constitutive exclusion of Csk from Hck-positive membrane microdomains that promotes proliferation and AP-1 induction via a phosphoinositide-3-kinase–independent pathway (7). AP-1 induction occurs exclusively via the JNK pathway and this leads to permanent c-Jun and ATF-2 phosphorylation (5). Moreover, the reduced metastatic potential of attenuated Theileria-infected macrophages correlates with altered AP-1 induction with respect to the mmp9 promoter (8), suggesting a role for certain AP-1 dimers in parasite-provoked tumor development. Here, we have examined the contribution of JNK > c-Jun signaling to the transformed phenotype of Theileria parva–infected B cells, and we find that JNK activation and c-Jun induction have overlapping, but nonidentical antiapoptotic roles in B cell survival. Over and above an antiapoptotic role, decreased c-Jun expression correlates with the impaired ability of infected B cells to degrade synthetic matrix in vitro, and to form tumors in a lymphoid mice (deficient in the recombinase-activating gene 2 and the common cytokine receptor 
chain; denoted Rag2/c mice). These data argue for a role for JNK 
c-Jun induction in Theileria-dependent B cell survival and metastasis.
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Materials and Methods
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Cells and cell culture. TpMD409.B2 is a T. parva Muguga-infected B-cell clone (B2) and the B cell characteristics of this line grown in our laboratory have been confirmed (9). Clone r8812 is a cloned B cell line, where 
169 c-Jun expression is constitutive. Pool 9 is a pool of infected B cell clones, which was generated by retroviral transduction of 169 c-Jun. Primary bovine B cells were sorted to 99% purity after labelling with a monoclonal antibody to bovine CD21 on a FACSAria (BD Biosciences, Oxford, United Kingdom).
Immunoblotting, inhibitors, and reagents. The JNK inhibitor, SP600125 (Sigma, St. Louis, MO), was added at 25 µmol/L every 6 hours for three times (18 hours), and anisomycin (Calbiochem, La Jolla, CA) was added at 50 ng mL–1 for 30 minutes. The drug buparvaquone (BW 720c) was a gift from Vet GmbH (Mallinchrodt, Uxbridge, United Kingdom). BW720c was added at 50 ng mL–1 for 60 hours to eliminate the parasite (7). The antibodies used in immunoblotting were as follows: anti-c-Jun (sc1694, Santa Cruz Biotechnology, Santa Cruz, CA), anti-Mcl-1 (sc-819, Santa Cruz Biotechnology), anti-Flag M2 (F1804, Sigma-Aldrich), anti c-IAP1 (BD PharMingen, San Diego, CA), and anti-actin (MAB1501, Chemicon International, Temecula, CA).
Transient transfection experiments and luciferase assays. Transient transfection experiments were carried out using a 3x TREcoll-luciferase reporter plasmid (10 µg; ref. 10), GFP-H2B (10 µg; ref. 11), pGL2luc basic (10 µg), pcDNA3-Flag-JNK-APF (20 µg; ref. 12), and pcDNA3 (20 µg; Invitrogen). Cytomegalovirus-driven ß-galactosidase-expressing vector (5 µg) was included in each sample for the standardization of transfection efficiency. For luciferase assays, cells were harvested 48 hours after transfection and luciferase activity was assayed in a microplate luminometer (Micro Lumat Plus LB96v, Berthold, Bacl, Wildbacl, Germany) using a Luciferase assay reagent (E1483, Promega, Madison, WI). Luciferase activity was compared with the basal levels obtained for pGL2-transfected cells.
Fluorescence-activated cell sorting analysis of infected and noninfected bovine B cells. Forty hours after transfection of T. parva-infected B cells, a total of 10,000 cells were acquired and fluorescence-activated cell sorting analysis with Annexin V-FITC (Annexin V FLUOS, Roche, Meylan, France) was done using CellQuest software. As apoptosis-positive controls, 2 x 105 cells were irradiated (450 Rad/cesium 137) 24 hours before fluorescence-activated cell sorting analysis. Bovine primary B cells were purified and incubated for 15 minutes at 37°C with a monoclonal antibody to bovine immunoglobulin light chain (IL-A58) to cross-link the B cell receptor, or left untreated. All cells were washed twice with PBS, before either were left untreated, or treated with SP600125 (25 µmol/L in DMSO), anisomycin (50 ng mL–1), or a combination of both. Cells treated with SP600125 were washed every 6 hours, resuspended in fresh medium, and fresh SP600125 was added.
In vitro assay for invasion. This assay is based on the ability of infected cells to penetrate and cross a layer of reconstituted extracellular matrix (Matrigel, Sigma), which was located as a thin coating over an 8-mm filter between the two sections of a Boyden-type chamber (Transwell, Costar Europe, Badhoevedorp, the Netherlands). To set up the assay, 5 x 105 cells were seeded into the upper chamber and left for 24 hours. After this time, the number of cells that had migrated into the bottom chamber was counted.
Tumor growth, metastasis, and histology in mice. Theileria transformed B cells expressing Flag 169 c-Jun (Pool9), or parental cells (wt) were washed in PBS and injected s.c. (1 x 106 in 0.2 mL of PBS) into 6-week-old Rag2/c (H-2k) female mice. Three independent experiments were done, such that each cell condition was injected in a total of 14 mice. Mice were sacrificed and examined 4 weeks or 8 weeks after injection (experiment 1 and experiments 2 and 3, respectively). For the detection of metastatic lesions, kidneys, spleens, as well as lungs and hearts were dissected. Tumor samples were fixed in 4% paraformaldehyde and embedded in paraffin for histopathologic examination. Serial 5-µm sections were cut and stained with H&E using standard procedures.
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Results
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JNK activation is antiapoptotic in T. parva-transformed B cells. Permanent JNK activation by Theileria parasites leads to sustained c-Jun phosphorylation and nuclear localization of the transcription factor (10). This implies that JNK induction plays a pivotal role in Theileria-induced lymphocyte transformation. T. parva-infected B cells were, therefore, treated thrice every 6 hours with SP600125, a well-established JNK inhibitor, and B cell apoptosis was measured by Annexin V staining (Fig. 1
). The inhibition of JNK generated significant (3-fold increase) apoptosis (Fig. 1A) compared with uninfected CD21+ B cells, where SP600125 only induces apoptosis following JNK activation (Fig. 1B). The ability of both SP600125 and JNK-APF (12) to down-regulate endogenous AP-1 activation of T. parva-transformed B cells was verified (Fig. 1C). Thus, in T. parva-infected B cells, as in healthy noninfected CD21+ B cells, once JNK is activated, it mediates a survival response and its inhibition leads to B cell apoptosis.
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Figure 1. JNK inhibition provokes apoptosis of T. parva-infected B cells. A, Theileria-transformed B cells were treated with the specific JNK inhibitor, SP600125, and apoptosis was measured by the degree of Annexin V staining. Six hours of SP600125 treatment induced apoptosis in 40% of the treated cells, compared with spontaneous apoptosis of 15% of the untreated infected control lymphocytes. B, SP600125 only induces B cell apoptosis following JNK activation in noninfected B lymphocytes. CD21-purified uninfected bovine B cells were either left untreated, or treated with anisomycin (50 ng mL–1) to activate them and also treated or not with SP600125 (25 µmol/L in DMSO) to inhibit JNK. Data are expressed as the percentage of cells reacting with Annexin V and one can observe that maximum apoptosis due to SP600125-mediated JNK inhibition occurs only following anisomycin stimulation, as anisomycin or SP600125 on their own generated close to background levels of apoptosis. C, SP600125-mediated JNK inhibition induces a drop in AP-1 activation in T. parva-infected B cells. Theileria-induced transformation leads to constitutive AP-1 activation, as measured by TRE-driven luciferase activity (TRE-luc). Treatment of T. parva-infected B cells with SP600125 under conditions that provoked apoptosis also leads to a reduction in AP-1 transactivation. As a control, we compared SP600125 inhibition of AP-1 to that induced by overexpression of a dominant-negative JNK construct (JNK APF) following transient transfection of T. parva-infected B cells.
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Permanent c-Jun induction contributes to the Theileria-dependent antiapoptotic response of infected B cells. We created infected B cells lines, where the expression of dominant-negative c-Jun (169) could be controlled by either the addition, or withdrawal, of tetracycline and we even obtained lines with constitutive 169-c-Jun expression. To exclude any nonspecific clonal effects, pools of infected B cell clones were generated by retroviral transduction of 169-c-Jun (Fig. 2
). Both in the cloned B cell line (r8812) and pool of clones (Pool 9), the induction of 169-c-Jun (monitored by Flag-epitope expression) was trans-dominant-negative on endogenous c-Jun levels (Fig. 2B). Thus, 169-c-Jun expression reduces the levels of c-Jun, an established c-Jun target gene (13), without noticeably affecting the proliferation of Theileria-transformed B cells.
As JNK activation is antiapoptotic (Fig. 1), we suspected that 169-c-Jun induction might sensitize Theileria-infected B cells to apoptosis and examined 169-c-Jun expressing B cells for amounts of antiapoptotic proteins (Fig. 2B) and estimated B cell apoptosis upon buparvaquone-induced parasite death (Fig. 2C). Mcl-1 and c-IAP were reduced compared with actin in 169-c-Jun expressing B cells, with a slightly more marked drop being observed for the pool of clones (Fig. 2B). Consistently, buparvaquone-induced parasite death generated significantly more apoptosis in 169-c-Jun expressing B cells (Fig. 2C, b, 50.3%) compared with drug-treated infected controls (a, 17.8%), and this was more pronounced with Pool 9 (b) versus the r8812 cloned line (d) that displayed 30.8% versus 19.7% for control (c). Thus, inhibition of c-Jun leads to a drop in the expression of Mcl-1 and c-IAP and concomitantly enhanced sensitivity to apoptosis upon drug-induced parasite death.
Inhibition of c-Jun results in reduced metastatic potential in vitro. Theileria-infected lymphocytes are invasive and the fact that 169-c-Jun expressing B cells proliferate normally allowed us to measure their metastatic potential in matrigel chamber assays (Fig. 3
). Infected B cells harboring just the tetracycline repressor (D409B2r), digested matrigel equally well in the presence, or absence, of doxycycline and were given an index of 1 (Fig. 3B). Two independent cell lines (r1 and r2), in which the addition of doxycyline induced 169-c-Jun expression and one cell line (t1), in which doxycycline repressed 169-c-Jun induction, all showed a 40% to 50% reduction in the capacity of infected B cells to traverse matrigel (Fig. 3B). This implies that Theileria-dependent c-Jun induction contributes to infected B cell invasiveness.
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Figure 3. Inhibition of c-Jun results in reduced metastatic potential in vitro. A, T. parva-infected B cell lines were produced, where expression of dominant-negative c-Jun (Flag-169) could be controlled by either the addition (+), or withdrawal of tetracycline (–), together with lines, where 169-c-Jun expression was constitutive. Two independent cell lines, where the addition of doxycyline induced 169-c-Jun expression ( r1 and r2), and one cell line, where doxycycline repressed 169-c-Jun induction (t1). B, all Flag-169 expressing T. parva-infected B cells showed a 40% to 50% reduction in the capacity of infected B cells to traverse matrigel, compared with infected B cells harboring just the tetracycline repressor (D409B2r), which digested matrigel equally well in the presence, or absence, of doxycycline and was given an index of 1.
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Inhibition of c-Jun results in reduced tumor formation in vivo. As Theileria-infected leukocytes could form tumors in immunocompromised mice (14), we tested the capacity of the pool of clones expressing 169-c-Jun to form tumors in a lymphoid Rag2/c mice (15). Theileria-infected B cells give rise to large tumors at the site of injection (Fig. 4A
). Only 3 out of 14 mice (1 of 4, 1 of 5, and 1 of 5) injected with Pool 9 of 169 expressing T. parva-infected B cells developed tumors within the 8-week period, compared with 9 out of 14 (4 of 4, 3 of 5, and 2 of 5) for the "wild-type" infected B cells (Fig. 4B). Moreover, the 169 expressing transformed B cells appeared at a reduced rate, and on average, were smaller (2.5 versus 3.5 cm). Finally, the invasion of kidneys could be observed in some mice (one of three and one of two) injected with parental T. parva-infected B cells, but not in either of the three mice that developed 169-c-Jun–derived tumors. Taken together, these in vivo data show that ablation of Theileria-dependent c-Jun induction renders parasite-transformed B cells much less aggressive in vivo.
Theileria-transformed B cells are invasive in Rag2/c mice. Histology was done on the tumors arising from wild-type Theileria-infected B cells (Fig. 4C): both at the site of injection (left), as well as in the kidneys (right). Top left, a representative macroscopic view of a large s.c. B lymphoma excised from the point of inoculation (Fig. 4). The middle (x40) and bottom panels (x100) show different magnifications of microscopic views of large pleiomorphic B cells that have invaded muscle tissue. Invasion of Theileria-infected B cells into the kidneys leads to a marked increase in size of this organ due to a tumor mass in the polar region. A normal mouse kidney (right) is compared with a Theileria-infected kidney (left). The middle and bottom panels show a kidney excised from a mouse injected with the wild-type Theileria-infected B cells.
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Discussion
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Constitutive JNK activation is observed in all types of leukocyte transformed by Theileria and in many human lymphomas (1). In infected B cells, JNK activation has been shown to contribute directly to the constitutive induction of the AP-1 transcription factor, including c-Jun and c-Fos subunits (10). The potential of JNK to phosphorylate and transactivate transcription factors in addition to c-Jun might explain why pharmacologic inhibition of JNK leads to infected B cell apoptosis (Fig. 1), whereas constitutive expression of a transactivation-compromised c-Jun mutant (169-c-Jun) only sensitizes infected B cells to death induced by buparvaquone treatment (Fig. 2C). Parasite-dependent JNK activation and c-Jun induction therefore have overlapping, but nonidentical, antiapoptotic roles in Theileria-induced B cell transformation.
A dissociation between JNK-only and JNK/c-Jun transcriptional targets has been observed in primary human fibroblasts (16). In human fibroblasts, disruption of the JNK/c-Jun interaction down-regulated the expression of the antiapoptotic proteins, hIAP-1 and hIAP-2, and c-IAP levels are similarly down-regulated in T. parva-infected B cells that constitutively expressed 169-c-Jun (Fig. 2C). We recently showed that Mcl-1 plays a major antiapoptotic role in T. parva-infected B cells and showed that c-Myc is induced in a JNK-dependent fashion (17, 18). The resemblance with human B lymphomas is striking, as their survival and proliferation has also been shown to depend on JNK-mediated Myc induction (19). Thus, important B cell survival factors are induced following JNK activation in both Theileria-transformed B cells and human B lymphomas.
Theileria annulata–infected macrophages grown in long-term culture slowly lose their metastatic potential and are used as attenuated vaccine lines in the fight against tropical Theileriosis (8). We therefore tested the capacity of T. parva-infected 169-c-Jun expressing B cells to degrade the synthetic matrix and observed a 40% to 50% reduction in their capacity to traverse metrigel (Fig. 3). Consistently, only 3 out of 14 mice developed tumors when infected with 169-c-Jun expressing B cells (Fig. 4). Histology done on the s.c. tumors showed large s.c. B lymphomas composed of large pleiomorphic B cells infiltrating the muscle. Moreover, invasion of the kidneys led to a marked increase in size due to tumor mass in the polar region of this organ. Taken together, the in vitro and in vivo data strongly support a role for c-Jun induction in the aggressiveness of Theileria-transformed B cells, and they argue that c-Jun induction could contribute to the metastatic potential of human B lymphomas, most likely although not exclusively, through the induction of matrix metalloproteinases (20). The study of Theileria-induced transformation should provide insights into our understanding and treatment of cancer of lymphoid cells in humans.
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Acknowledgments
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Grant support: J.P. Di Santo receives support from the Institut Pasteur, INSERM, and the Ligue Nationale contre le Cancer as an Equipe Labellisée and G. Langsley receives support from the Centre National de la Recherche Scientifique, INSERM, and the Wellcome Trust under their Special Initiative for Tropical Animal Diseases. D. Werling also acknowledges Wellcome Trust support. R. Lizundia acknowledges support from L'Académie Nationale de Médecine and a short-term research fellowship from the Royal Society and COST Action 857.
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.
We thank Frederic Dessauge for help in preparing the figures, Patrick Ave for the histology, Jonathan Weitzman for discussion and comments on the article, Jonathan Ham for the 169 c-Jun construct, Roger Davis for the dominant-negative JNKAPF plasmid, and Hermann Bujard for help in creating the tet-inducible B cell lines.
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Footnotes
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Note: R. Lizundia and M. Chaussepied contributed equally to this work.
M. Chaussepied is currently at the Institute of Cell and Molecular Science, Center for Cutaneous Research, Queen Mary University of London, 4 Newark Street, London E1 2AT, United Kingdom.
Received 10/26/05.
Revised 3/28/06.
Accepted 4/19/06.
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Abstract
Introduction
