Sensitization of interferon-γ induced apoptosis in human osteosarcoma cells by extracellular S100A4
© Pedersen et al; licensee BioMed Central Ltd. 2004
Received: 18 May 2004
Accepted: 19 August 2004
Published: 19 August 2004
S100A4 is a small Ca2+-binding protein of the S100 family with metastasis-promoting properties. Recently, secreted S100A4 protein has been shown to possess a number of functions, including induction of angiogenesis, stimulation of cell motility and neurite extension.
Cell cultures from two human osteosarcoma cell lines, OHS and its anti-S100A4 ribozyme transfected counterpart II-11b, was treated with IFN-γ and recombinant S100A4 in order to study the sensitizing effects of extracellular S100A4 on IFN-γ mediated apoptosis. Induction of apoptosis was demonstrated by DNA fragmentation, cleavage of poly (ADP-ribose) polymerase and Lamin B.
In the present work, we found that the S100A4-expressing human osteosarcoma cell line OHS was more sensitive to IFN-γ-mediated apoptosis than the II-11b cells. S100A4 protein was detected in conditioned medium from OHS cells, but not from II-11b cells, and addition of recombinant S100A4 to the cell medium sensitized II-11b cells to apoptosis induced by IFN-γ. The S100A4/IFN-γ-mediated induction of apoptosis was shown to be independent of caspase activation, but dependent on the formation of reactive oxygen species. Furthermore, addition of extracellular S100A4 was demonstrated to activate nuclear factor-κB (NF-κB).
In conclusion, we have shown that S100A4 sensitizes osteosarcoma cells to IFN-γ-mediated induction of apoptosis. Additionally, extracellular S100A4 activates NF-κB, but whether these events are causally related remains unknown.
The S100 protein family consists of at least 21 small, acidic, Ca2+-binding proteins with different expression patterns and apparently diverse functional and biological properties . The S100A4 protein has been associated with increased metastatic capacity of cancer cells [2–4], but how S100A4 exerts the metastasis-promoting effects is still incompletely understood. S100A4 has been shown to interact with a number of cytoskeleton-associated proteins, including non-muscle myosin , actin  and non-muscle tropomyosin , thereby possibly affecting cell motility. In addition, we have previously demonstrated an association between S100A4, matrix metalloproteinases and the invasive capacity of osteosarcoma cells . It has also been reported that S100A4 can be secreted, and suggested extracellular functions include induction of angiogenesis , stimulation of cell motility , and stimulation of neurite outgrowth . Moreover, we have recently demonstrated nuclear localization of S100A4, and an association between nuclear expression and tumor stage in colorectal cancer , indicating other, yet undiscovered, functions of S100A4. Finally, S100A4 has been reported to interact with the tumor suppressor protein p53 and to modulate transcription of downstream target genes, thus influencing p53-mediated apoptosis .
Interferon-gamma (IFN-γ) is a pleiotropic cytokine secreted from activated T lymphocytes and natural killer cells. It can activate and suppress a number of target genes, leading to various effects, including inhibition of viral replication, activation of immune cells and induction of cell cycle arrest and apoptosis [14, 15]. Apoptosis is a process of programmed cell death characterized by chromatin condensation and DNA fragmentation, plasma membrane blebbing and cell shrinkage. One of the central executioners of the apoptotic pathway are the caspases . It has, however, become evident that a number of caspase-independent pathways exist, leading to programmed cell death involving cathepsins , apoptosis inducing factor , calpains, AP24 and other serine proteases . Evidence has been provided showing that IFN-γ is able to induce programmed cell death by both caspase-dependent and -independent pathways, e.g. through cathepsin D , caspase-1 , TNF-related apoptosis-inducing ligand (TRAIL)  and Fas/FasL .
Searching for cytokines and signal transduction modulators affecting S100A4 expression, we recently discovered that IFN-γ downregulated S100A4 transcription and induced apoptosis in the human osteosarcoma cell line OHS . In the corresponding anti-S100A4 ribozyme-transfected cell line II-11b , apoptosis induction was remarkably lower, and these findings prompted us to investigate whether S100A4 could affect IFN-γ-mediated apoptosis. In the present study, we show that S100A4 can be secreted from these human osteosarcoma cells, and that extracellular addition of rS100A4 sensitizes cells to apoptosis induced by IFN-γ. Furthermore, we demonstrate that this cell death pathway is independent of caspases, but possibly dependent upon NF-κB transactivation and generation of reactive oxygen species (ROS).
Cell culture and treatment
The human osteosarcoma cell line OHS and its anti-S100A4 ribozyme transfected counterpart II-11b have been described previously . Cell lines were cultivated in RPMI-1640 (Bio Whittaker, Verviers, Belgium) containing 10% fetal bovine serum (FBS; Biochrome KG, Berlin, Germany), 1 mM Hepes, and 2 mM Glutamax (GIBCO BRL, Life Technologies, Paisley, UK). For all experiments, subconfluent cultures were trypsinated and seeded at 1.5 × 104 cells/cm2. After overnight incubation, the culture medium was replaced with medium in presence or absence of IFN-γ and recombinant S100 proteins, and harvested as indicated in the text. Where indicated, protease inhibitors or antioxidants were added to the cell culture simultaneously as IFN-γ.
Human recombinant IFN-γ, L-NMMA, zVAD-fmk, zYVAD-fmk, zVDVAD-fmk, zDEVD-fmk, zVEID-fmk, zIETD-fmk, zLEHD-fmk, zFA-fmk and E64 were purchased from Calbiochem (San Diego, CA, USA). N-acetylcysteine was from Sigma Chemical Co (St Louis, MO, USA).
Production of proteins
Histidine-tagged mouse recombinant S100A4 was cloned into the pQE30 vector (kindly provided by E. Lukanidin, Institute of Cancer Biology, Copenhagen, Denmark), expressed in E. coli, purified on a Ni2+-column and dialyzed against phosphate-buffered saline. A satisfactory degree of purity was confirmed by SDS polyacrylamide gel electrophoresis (SDS-PAGE) where a single band was visualized by silver staining. Verification of the identity of the protein was performed using matrix-assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI). Human recombinant S100A10 and S100A13 tagged with maltose-binding protein were kindly provided by C. S. Skjerpen (Dep. of Biochemistry, The Norwegian Radium Hospital, Oslo, Norway).
Cell viability was estimated by measuring metabolic activity using CellTiter 96® AQueous One Solution Reagent (MTS) (Promega, Madison, WI, USA) according to the manufacturer's manual. The absorbance at 490 nm was recorded using a Wallac 1420 Victor2 Multilabel counter (Wallac Oy, Turku, Finland).
Western blot analysis
Protein lysates were prepared in 50 mM Tris-HCl (pH 7.5) containing 150 mM NaCl and 0.1% NP-40 with 1 mM PMSF and 2 μg/ml each of pepstatin, aprotinin (Sigma Chemical Co, St Louis, MO, USA) and leupeptin (Roche Diagnostics, Mannheim, Germany). Total protein lysate from each sample was separated on 8–12% SDS-polyacrylamide gel electrophoresis, and transferred onto Immobilon-P membranes (Millipore, Bedford, MA, USA) according to the manufacturer's manual. As a loading and transfer control, the membranes were stained with 0.1% amidoblack. After blockage of non-specific binding sites with 10% non-fat dry milk in Tris-buffered saline with 0.25% Tween (TBST), blots were incubated for 1 h at room temperature with rabbit polyclonal anti-poly (ADP-ribose) polymerase (PARP; diluted 1:1000, Roche Diagnostics, Mannheim, Germany), mouse monoclonal anti-lamin B (0.3 μg/ml; Oncogene Research Products, Boston, MA, USA), mouse monoclonal anti-α-tubulin (0.3 μg/ml; Oncogene Research Products, Boston, MA, USA), rabbit polyclonal anti-caspase-1 (1:100; Santa Cruz Biotechnology, Santa Cruz, CA, USA), goat polyclonal anti-caspase-3 (1:2000; R&D Systems, Minneapolis, MN, USA), mouse monoclonal anti-caspase-8 (1:5000; Alexis Biochemicals, Montreal, Canada), mouse monoclonal anti-caspase-9 (1:1000; R&D Systems, Minneapolis, MN, USA), rabbit polyclonal anti-caspase-12 (1:2000; Oncogene Research Products, San Diego, CA, USA), mouse monoclonal anti-NFκB p65 (1:1000, Cell Signaling Technology Inc. Beverly, MA, USA) or mouse monoclonal anti-phospho-IκBα (Ser32/36) (1:2000, Cell Signaling Technology Inc. Beverly, MA, USA). After washing, the blots were incubated for 1 h at room temperature with a horseradish peroxidase-conjugated secondary antibody (DAKO, Glostrup, Denmark) diluted 1:5000. Anti-lamin B, anti-α-tubulin, anti-PARP, anti-caspase-1, anti-caspase-8, anti-NFκB p65 and anti-phospho-IκBα were diluted in TBST with 5% non-fat dry milk, anti-caspase-3 and anti-caspase-12 were diluted in TBS containing 0.05% Tween and 2% non-fat dry milk and anti-caspase-9 was diluted in TBS with 0.05% Tween, 1% non-fat dry milk and 1% BSA. Signals were visualized using the ECL chemiluminescence substrate (Amersham Pharmacia Biotech, Buckinghamshire, UK).
DNA fragmentation analysis
Cells were resuspended in lysis buffer (10 mM Tris-HCl pH 7.4, 10 mM NaCl, 10 mM EDTA, 0.5 % SDS and 0.5 μg/ml proteinase K) and incubated for 1 hour at 50°C. High molecular weight DNA was precipitated by adding 1 M NaCl and subsequently incubated overnight at 4°C. Samples were centrifuged for 30 min, 2700 g at 4°C, and supernatants collected. 95 % ethanol was added, and DNA precipitated overnight at -20°C. Samples were centrifuged for 10 min, 10 000 rpm at 4°C, and pellets were washed in 70 % ethanol and re-centrifuged. Thereafter, pellets were air-dried and dissolved in 10 mM Tris-HCl (pH 7.0), 15 mM NaCl, 1 mM EDTA and 0.2 mg/ml RNAse A, and incubated for 1 h at room temperature. DNA was separated by electrophoresis in 1.0 % agarose gel containing ethidium bromide and photographed under ultraviolet illumination.
Detection of S100A4 in cell culture medium
Cell culture medium from OHS and II-11b cells were harvested at 24, 48 and 72 hours, and immediately filtered using a 0.45 μm filter to discard cells in suspension. From each sample, 1.5 ml of medium was subjected to immunoprecipitation using 15 μg of rabbit polyclonal anti-S100A4 (DAKO, Glostrup, Denmark) or 15 μg rabbit polyclonal anti-p300 (Santa Cruz Biotechnology, Santa Cruz, CA, USA). Primary antibody binding was carried out in cell culture medium at 4°C overnight. Thereafter, antibody was precipitated using Protein A Sepharose beads for 1 h at 4°C and eluted in loading buffer. Samples were subjected to Western blot analysis as described above using rabbit polyclonal anti-S100A4 diluted 1:300 in TBST.
Transient transfection and plasmid constructs
The NF-κB reporter construct containing three NF-κB response elements (i.e., sites identical to the κB site from the Igκ light chain promoter) driving luciferase expression has been described previously . 1.0 × 106 II-11b cells were transiently transfected with 10 μg of the NF-κB reporter construct using electroporation (240 V). Thereafter, cells were seeded in 96-well plates at a density of 4.5 × 104 cells/cm2 and incubated in the absence or presence of rS100A4 and zFA-fmk. Cells were harvested 48 h later and assayed for luciferase activity using the Luciferase Assay System (Promega, Madison, WI, USA) according to the manufacturer's manual.
All statistical analyses were performed using Student's t-test. P-values less than 0.05 were considered to be statistically significant.
OHS cells are more sensitive than II-11b cells to IFN-γ-mediated suppression of cell viability
IFN-γ induces apoptosis in OHS Cells
Detection of S100A4 in cell culture medium
Sensitization of IFN-γ-mediated apoptosis by extracellular S100A4
IFN-γ-mediated apoptosis in OHS dells is caspase-independent
Reactive oxygen species mediate IFN-γ-induced apoptosis
The caspase inhibitors used in the experiments above were solved in dimethyl sulfoxide (DMSO), and therefore DMSO was included as a negative control. Surprisingly, a significant inhibition of IFN-γ-induced apoptosis was observed using 0.25 % DMSO (Fig. 7). One of the known biological properties of DMSO is scavenging of hydroxyl radicals, indicating that the generation of reactive oxygen species (ROS) could be implicated in the observed induction of apoptosis. Furthermore, treatment with the commonly used antioxidant N-acetylcysteine significantly suppressed the IFN-γ-induced cell death (Fig. 7), whereas the nitric oxide synthase inhibitor L-NMMA had no effect (data not shown). Notably, zVAD-fmk was recently shown to possess potent antioxidant effects at high concentrations  possibly explaining its inhibitory effects shown above.
IFN-γ-mediated apoptosis in OHS cells is independent of cathepsin B, but possibly mediated by NF-κB
IFN-γ induces apoptosis in a variety of different cell types, but some cells are less susceptible or even resistant to IFN-γ-mediated apoptosis. The reasons for this variation have not been clearly elucidated, and given the biological importance of IFN-γ, a better understanding of the mechanisms of IFN-γ-induced cell death is warranted. In the present study, we have demonstrated that the Ca2+-binding protein S100A4 sensitizes human osteosarcoma cells to IFN-γ-induced apoptosis. Furthermore, we have shown that the IFN-γ-mediated cell death is independent of caspases, but possibly mediated by reactive oxygen species. Finally, we have demonstrated that extracellular S100A4 can activate NF-κB through increased phosphorylation of IκBα, but whether this NF-κB transactivation is required for apoptosis induction remains unknown.
Several of the S100 proteins are released into the extracellular space, mostly by unknown mechanisms . S100A4 secretion by human osteosarcoma cells is in agreement with previous reports showing that S100A4 can be released from non-malignant as well as tumor cells [9, 31, 32]. The apoptosis-inducing properties of extracellular S100A4 are, however, novel findings, emphasizing the multiple functions of this protein. Other extracellular S100 proteins also exert multiple effects, including proinflammatory activity, chemotaxis, neurite extension, stimulation of angiogenesis, and regulation of cell survival . Proapoptotic activity has, to our knowledge, only been demonstrated previously for S100A1, S100B  and S100A8/S100A9 . S100B induces apoptosis by interaction with the multi-ligand cell surface receptor RAGE (a member of the immunoglobulin superfamily) . RAGE also binds S100A12 , whereas no cell surface receptor for S100A4 has been identified so far. In view of the significant homology between S100 proteins, S100A4 could possibly bind to and activate RAGE. However, treatment with anti-RAGE IgG  up to 50 μg/ml had no inhibitory effect on apoptosis induction (data not shown), and higher concentrations were toxic to the cells. Hence, another cell surface receptor might mediate S100A4-induced sensitization of apoptosis, and in line with this, RAGE-independent actions were recently demonstrated for S100B . Notably, mechanisms distinct from ligand-receptor interactions can also propagate proapoptotic signals. S100A8/S100A9 induced apoptosis even when a dialysis membrane hindered contact with the cells, possibly by binding Zn2+ or other divalent cations .
Addition of 20 μg/ml rS100A4 (1.5 μM) to the cell medium of II-11b cells was required to induce apoptosis upon IFN-γ-treatment. Comparably, micromolar amounts of S100B and S100A8/A9 were needed to induce cell death [33, 34]. Also S100A4-mediated neurite extension  as well as stimulation of angiogenesis  were shown to require micromolar concentrations of recombinant protein. Whether native extracellular S100A4 is present at these concentrations in our experiments is unknown, as secreted S100A4 was not quantitatively estimated.
In many cases, stimulation of tumor cells with a single proapoptotic signal is not sufficient for induction of programmed cell death. On the other hand, a number of cytokines and other proapoptotic signal substances can increase the cells' sensitivity to other apoptosis-inducing agents, thus initiating the cell death program. IFN-γ induces apoptosis in synergism with a wide variety of such agents, and particularly members of the tumor necrosis factor (TNF) superfamily have been studied, e.g., TNF-α , FasL , LIGHT  and TRAIL . Our work adds a novel proapoptotic signaling molecule to the list of agents acting in synergism with IFN-γ to induce programmed cell death. The mechanisms by which S100A4 sensitizes the tumor cells to apoptosis induction are not completely elucidated. Recently, Grigorian et al demonstrated that S100A4 interacts with the tumor suppressor protein p53 to enhance p53-dependent apoptosis. The proposed mechanism was based on modulation of p53-dependent transactivation of target genes . The osteosarcoma cells used in our experiments harbor, however, a mutated p53 protein , thus, S100A4 seemingly enhance apoptosis through at least two distinct mechanisms. One possible explanation for the apoptosis sensitizing effects of S100A4 is that the protein positively modulates IFN-γ-signaling in general. By studying the regulation of S100A4 expression, we have demonstrated that extracellular S100A4 enhances IFN-γ-mediated suppression of S100A4 transcription (Pedersen et al., in preparation). These findings, in addition to the present work, suggest that secreted S100A4 could sensitize IFN-γ-signaling, and this possibility is currently under investigation. Previously identified sensitizers of IFN-γ-signaling include type I interferons (IFN-α/-β)  and IFN-γ itself . Hu et al. discusses, based on their experiments using peripheral blood mononuclear cells, that other factors probably also exist to sensitize IFN-γ-signaling. Interestingly, S100A4 is strongly expressed by T lymphocytes , but whether lymphocytes also secrete S100A4 remains to be investigated.
Our results suggest that S100A4-mediated NF-κB activation might be required for triggering the apoptotic process induced by IFN-γ. To support this hypothesis, we made attempts to inhibit NF-κB signaling by treatment with SN50, a peptide that contains the p50 NLS and selectively blocks nuclear translocation of NF-κB, but this lead to an increased fraction of apoptotic cells. Schotte et al. suggest that zFA-fmk has a promoter-specific NF-κB inhibitory effect , whereas SN50 potently blocks all NF-κB activity, possibly explaining the divergent results. In general, activation of NF-κB is regarded as an anti-apoptotic event and as such, a total suppression of NF-κB activity could be deleterious to cells. However, NF-κB apparently has a dual role in apoptosis regulation, and cell death induction by NF-κB has been reported in a variety of cell systems .
IFN-γ-induced apoptosis in OHS cells was shown to be caspase-independent by two different approaches: (i) no active forms of a number of caspases were detected; and (ii) caspase inhibitors were not able to suppress cell death triggered by IFN-γ. Even though the caspase cascade was not activated, well-known hallmarks of apoptosis were identified. DNA fragmentation and Lamin B cleavage have previously been shown to occur independent of caspase activation [44, 45], whereas PARP cleavage has been regarded as a caspase-indispensable event. Cleavage of PARP to an 89-kDa fragment was however evident, but the observed low level activation of caspase-9 was, due to the lack of effect when adding the specific caspase-9 inhibitor, not considered crucial, possibly implicating other proteases than caspases in PARP inactivation. Finally, experiments using the antioxidant NAC indicated that ROS are involved in S100A4/IFN-γ-mediated triggering of apoptosis. In light of recent reports demonstrating that both S100B and S100A8/S100A9 induced apoptosis in an oxidant-dependent manner this result is highly interesting [33, 46].
In conclusion, we have demonstrated that extracellular S100A4 induces NF-κB transactivation and possesses proapoptotic activity through sensitization of IFN-γ-induced apoptosis, but whether activation of NF-κB is required for the observed sensitization of cell death is still unknown. Even though the precise physiological role of the apoptosis sensitizing effect of S100A4 awaits further studies, it highlights yet another area of research in the attempts to elucidate the complex biological roles of S100A4.
We gratefully acknowledge the generous gift of the pQE30-S100A4 expression construct from Dr. E. Lukanidin (Institute of Cancer Biology, Copenhagen, Denmark), recombinant S100A10 and S100A13 from C. S. Skjerpen (The Norwegian Radium Hospital, Oslo, Norway) and anti-RAGE IgG from Dr. A. M. Schmidt (Columbia University, New York, USA). The authors would also like to thank Dr. Dave Warren for production of recombinant S100A4, Ida Grotterød for excellent technical assistance and Dr. Yvonne Andersson for helpful discussions. The Norwegian Cancer Society, The Research Council of Norway and Stiftelsen Sophies Minde financially supported the study.
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