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1 Department of Internal Medicine I, Division of Hematology and Hemostaseology, 2 Department of Radiation Therapy and 3 Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, and 4 St. Anna Children’s Hospital, Vienna, Austria
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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During the past few years, a number of attempts have been made to identify critical genes and factors that regulate survival and apoptosis in CML cells (6) . Apart from external factors (cytokines; Ref. 7 ), a number of cellular molecules have been implicated in the regulation of apoptosis in BCR/ABL-transformed cells. Likewise, depending on the cell type analyzed, members of the bcl-2 family (bcl-xL, bcl-2, and A1) reportedly counteract apoptosis (8, 9, 10, 11) . However, little is known about the relative contribution of each of these molecules to survival of leukemic cells. In addition, some of these molecules may only be expressed in leukemic cells in a subset of patients with CML (12) . Therefore, it seems of importance to further search for new antiapoptotic molecules expressed in CML cells.
Heme oxygenase-1 (HO-1) is an inducible stress protein that catalyzes the degradation of heme to carbon monoxide (CO), biliverdin, and iron (13 , 14) . Recently, HO-1 has been implicated in the regulation of apoptosis in various mesenchymal cells (14) . Although the precise mechanisms of HO-1-dependent survival are not known, recent data suggest that antiapoptotic effects of HO-1 are mediated through heme degradation products.
Thus far, most studies analyzing the role of HO-1 as an antiapoptotic molecule have focused on endothelial cells and fibroblasts (15, 16, 17, 18, 19) . More recent data suggest, however, that cancer cells in solid tumors can also express HO-1 (20, 21, 22, 23) . In the present study, we show that CML cells express HO-1 in a constitutive manner and that the BCR/ABL oncogene promotes HO-1 gene expression. In addition, our data suggest that HO-1 plays a role in BCR/ABL-dependent survival of CML cells. Thus, HO-1 may represent a novel BCR/ABL-dependent, antiapoptotic effecter molecule and potential target in CML.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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48 h. All experiments with Ton.B210-X cells were performed in UltraCulture medium (BioWhittaker, Walkersville, MD). The Philadelphia chromosome-positive, CML-derived K562 cell line and BCR/ABL-transformed Ba/F3 cells (Ba/F3p210 cells) were maintained in RPMI 1640 with 10% FCS at 37°C and 5% CO2. To inhibit BCR/ABL tyrosine kinase activity, cells were exposed to 1 µM STI571 (kindly provided by Novartis Pharma AG, Basel, Switzerland) for 16–48 h. To induce expression of HO-1, cells were incubated with hemin (10–20 µM; Sigma, St. Louis, MO) for 16–48 h at 37°C and 5% CO2. After exposure to compounds, cells were analyzed for survival and/or subjected to Northern or Western blot analysis.
Isolation and Culture of Primary Cells.
Primary leukemic cells were obtained from 15 patients with untreated chronic phase CML. Informed consent was obtained before blood donation. Peripheral blood mononuclear cells were isolated by Ficoll density centrifugation. Isolated peripheral blood mononuclear cells were cultured in RPMI 1640 with 10% FCS at 37°C and 5% CO2.
Immunocytochemistry.
Immunocytochemistry was performed on cytospin preparations of primary leukemic cells (bone marrow and peripheral blood mononuclear cells) obtained from 6 patients with chronic phase CML. Acetone-fixed slides were incubated with a polyclonal rabbit anti-HO-1 antibody (work dilution: 1:1000; Stressgen Biotechnologies Corp., Victoria, British Columbia, Canada) for 60 min. After washing, slides were incubated with a biotinylated goat antirabbit IgG (Biocarta, San Diego, CA) for 30 min and then with streptavidin-alkaline-phosphatase complex (Biocarta) for another 30 min. Neofuchsin (Nichirei, Tokyo, Japan) was used as chromogen. Slides were counterstained in Mayer’s hemalaun. In control experiments, slides were preincubated with a HO-1 blocking peptide (Stressgen) before antibody exposure.
HO-1 Reporter Gene Assay.
To determine HO-1 promoter activity, the HO-1-luc construct (Ref. 26
; a kind gift of Shigeru Takahashi, Scripps Research Institute, La Jolla, CA; 10 µg) was transfected together with a pCMV-ßGAL construct (10 µg) by electroporation (0.35 kV, 960 µF, Gene Pulser; Bio-Rad, Hercules, CA) into Ton.B210-X cells (1 x 107 in 800 µl). Thereafter, cells were either maintained in the presence or absence of doxycycline (1 µg/ml) for 18 h in UltraCulture medium. Cells were then harvested, and the pellets were resuspended in lysis buffer (Promega, Madison, WI). Lysates (30 µl) were incubated with 100 µl of luciferase assay buffer [25 mM glycylglycine, 15 mM potassium phosphate (pH 7.8), 15 mM MgSO4, 4 mM EGTA, 2 mM ATP, and 1 mM DTT] and 100 µl of D-luciferin (0.3 mg/ml; PharMingen, San Diego, CA). Luciferase activity was determined by an automated luminometer (Wallac 1420 multilabel counter; Perkin-Elmer, Turku, Finland). Plasmid pCMV-ßGAL (Invitrogen, Carlsbad, CA) was used as a reporter for transfection efficiency. For determination of ßGAL-activity, we used the Invitrogen ßGAL Assay Kit (Invitrogen). HO-1 reporter gene activity was given as a ratio of luciferase activity:ßGAL-activity.
Northern Blot Analysis.
Total RNA was extracted from Ton.B210-X cells or primary CML-derived peripheral blood mononuclear cells using Trizol (Life Technologies) according to the manufacturer’s instructions. Northern blotting was performed essentially as described (25)
. In brief, 20 µg of total RNA were size fractionated on 1% formaldehyde-agarose gels and transferred to nylon membranes (Hybond N; Amersham, Aylesbury, United Kingdom) as described by Chomczynski (27)
. Membranes were hybridized in rapid-hyb buffer (Amersham). Hybridization was performed with 32P-labeled cDNAs specific for HO-1 and ß-actin. Primers for PCR amplification of probes were as follows: murine HO-1: 5'-CCTCACTGGCAGGAAATCAT-3' (forward) and 5'-TCTCTGCAGGGGCAGTATCT-3' (reverse); murine ß-actin: 5'-GACG-GCCAGGTCATCACTAT-3' (forward) and 5'-AGGGAGACCAAAGCC-TTCAT-3' (reverse); human HO-1: 5'-ATGGAGCGTCCGCAACCCGA-3' (forward) and 5'-GCATAAAGCCCTACAGCAAC-3' (reverse); human ß-actin: 5'-ATGGATGATGATATCGCCGCG-3' (forward) and 5'-CTAGAAGCATTTGCGGTGGACGATGGAGGGGCC-3' (reverse). Labeling was performed using the Megaprime kit (Amersham). Blots were washed in 0.2 x SSC [1 x SSC = 150 mM NaCl and 15 mM sodium citrate (pH 7.0)] with 0.1% SDS at 42°C for 2 x 30 min and at 62°C for another 30 min. Bound radioactivity was visualized by exposure to Biomax MS film (Eastman Kodak, Rochester, NY) at –80°C using intensifying screens (Kodak). mRNA expression levels were quantified by densitometry of autoradiograms using the E.A.S.Y. Win32 software (Herolab, Wiesloch, Germany).
Preparation of Cell Lysates and Western Blotting.
Cells were washed in 0.9% NaCl and then lysed by distilled water and freeze thawing. Cellular proteins were separated under reducing conditions by SDS-PAGE and then transferred to a nitrocellulose membrane (Protran, Schleicher & Schuell Bioscience, Keene, NH) in buffer containing 25 mM Tris, 192 mM glycine, and 20% methanol at 4°C. The membrane was blocked for 1 h in 3% BSA. After incubation with a rabbit anti-HO-1 polyclonal antibody (Stressgen), the membrane was exposed to goat antirabbit IgG (Amersham). To confirm equal loading, membranes were reprobed with a rabbit antiactin antibody (Sigma). Chemoluminescence was detected by exposure to Biomax MS film (Kodak).
Transient Expression of HO-1 and Cell Sorting.
K562 cells (5 x 106 cells in 800 µl) were transfected by electroporation (960 microfarads, 200 V; Gene-Pulser Bio-Rad) with 15 µg of pCDNA3-HO-1 (kindly provided by Shigeki Shibahara, Tohoku University School of Medicine, Sendai, Japan; Ref. 28
) or empty pCDNA3 vector and with 10 µg of a plasmid containing enhanced green fluorescent protein (Clontech, Palo Alto, CA). After electroporation (24 h), enhanced green fluorescent protein-expressing cells were sorted on a high-speed cell sorter (FACSAria; Becton Dickinson, Heidelberg, Germany). After sorting, cells were cultured in RPMI 1640 plus 10% FCS at 37°C and 5% CO2 for 24 h. Then, cells were split and cultured in the absence or presence of STI571 (500 nM) for another 24 h at 37°C and 5% CO2. Thereafter, the percentage of apoptotic cells was assessed by annexin V-staining. For this purpose, cells were washed in PBS and then incubated with annexin V-APC (Alexis Biochemicals, Lausen, Switzerland) in binding buffer containing HEPES [10 mM (pH 7.4)], NaCl (140 mM), and CaCl2 (2.5 mM). Cells were then washed and analyzed by flow cytometry (FACSCalibur; Becton Dickinson).
Treatment of Cells with CO, Biliverdin, and Desferrioxamine (DFX).
K562 cells were grown in a humidified air atmosphere containing either 5% CO2 without CO or 5% CO2 together with 1% CO (kindly provided by AGA Linde Health Care, Lidingö, Sweden) as described by Otterbein et al. (29)
for 48 h. During the first 3 h, cells were kept in CO-containing or control atmosphere without additional compounds. Then, various combinations of STI571 (1 µM), biliverdin (100 µM; Porphyrin Products, Logan, UT), DFX (100 µM; Novartis), or hemin (20 µM) were added. After 48 h, the percentage of apoptotic cells was determined.
Determination of Cell Viability and Apoptosis.
To investigate the function of HO-1 in BCR/ABL-dependent survival of leukemic cells, primary CML cells (patients in chronic phase CML, n = 3), K562, and Ba/F3p210 cells were analyzed. K562 and Ba/F3p210 cells were incubated with STI571 (1 µM) in the presence or absence of hemin (20 µM) at 37°C and 5% CO2 for 48 h. Primary CML cells were incubated with STI571 (1 µM) in the presence or absence of hemin (20 µM; Ref. 28
) at 37°C and 5% CO2 for 3 weeks. In these experiments, STI571 was replaced every 48 h, and hemin was replaced every 96 h. In addition, CML cells were cultured in the presence or absence of the HO-1 inhibitor zinc-(II)-deuteroporphyrin-IX-2,4-bisethyleneglycol (ZnDPPIX; Ref. 30
) at 37°C and 5% CO2 for 3 weeks. ZnDPPIX was applied at a concentration of 10 µM and replaced every 96 h. For determination of cell viability, cells were washed in PBS and stained with propidium iodide (1 µg/ml) before being subjected to flow cytometry (FACScan; Becton Dickinson). Cells were defined as being nonviable (propidium positive) when shifting above autofluorescence levels of unstained cells. Cell viability was also determined by the trypan blue exclusion test. The percentage of apoptotic cells was quantified on cytospin preparations (Wright-Giemsa stained). Apoptosis was defined according to conventional cytomorphological criteria (31)
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. As assessed by Northern blotting, HO-1 mRNA expression was detectable in all patients analyzed (n = 10). The BCR/ABL tyrosine kinase inhibitor STI571 (1 µM) counteracted HO-1 mRNA expression in leukemic cells (Fig. 1A)
, suggesting a possible role for BCR/ABL in HO-1 gene expression. Hemin, a potent inducer of HO-1, was found to up-regulate expression of HO-1 mRNA in primary CML cells (Fig. 1B)
. As determined by Western blotting, the HO-1 protein was found to be expressed in primary CML cells in 4 of 4 patients analyzed (Fig. 1C)
. Treatment of cells with STI571 (1 µM) for 16 h resulted in a substantial decrease in expression of the HO-1 protein (Fig. 1D)
. We next examined HO-1 protein expression in CML cells by immunocytochemistry. As expected, the HO-1 protein was detectable in leukemic cells by immunostaining in all CML patients (n = 6) analyzed (Fig. 2A)
. Preincubation of CML cells with a HO-1 blocking peptide abrogated HO-1 immunoreactivity (Fig. 2B)
, confirming the specificity of the antibody reaction. All in all, these data show that primary CML cells express HO-1 mRNA and the HO-1 protein in a constitutive manner and that HO-1 expression in these cells is sensitive to treatment with STI571, suggesting a potential role for BCR/ABL in HO-1 expression.
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2–3-fold increase in expression of HO-1 mRNA in these cells (Fig. 3A)
. We next asked whether induction of HO-1 by BCR/ABL would depend on transcriptional activation of the HO-1 gene. For this purpose, Ton.B210-X cells were transfected with a HO-1 reporter gene construct. After transfection, cells were split and either maintained in the presence or absence of doxycycline. As shown in Fig. 3B
, BCR/ABL significantly increased HO-1 promoter activity compared with starved cells. Similarly, the expression of BCR/ABL augmented HO-1 protein levels as shown by Western blot analysis (Fig. 3C)
. These data show that the BCR/ABL oncogene promotes HO-1 expression through transcriptional activation of the HO-1 promoter in Ton.B210-X cells.
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, induction of HO-1 by hemin was found to counteract STI571-induced cell death in K562 cells. In particular, exposure of K562 cells to STI571 (1 µM) for 48 h resulted in a substantial decrease of cell viability, and addition of hemin (20 µM) rescued these cells from STI571-induced cell death (Fig. 4A)
. Corresponding results were obtained with BCR/ABL-transformed Ba/F3 cells (data not shown). To show that hemin indeed leads to induction of HO-1 in STI571-treated cells, Northern blot experiments were performed. In these experiments, hemin-treated cells were found to express HO-1 mRNA in the absence as well as presence of STI571 in Ba/F3p210 cells (Fig. 4B)
, and the same was found to hold true for K562 cells (data not shown). To provide additional evidence for the protective effect of HO-1 (against STI571-induced apoptosis), K562 cells were transfected with a vector containing the HO-1 cDNA. As expected, the STI571-induced apoptosis of K562 cells was markedly reduced in HO-1-transfected K562 cells compared with cells transfected with the empty control vector (Fig. 5)
. All in all, these data suggest that HO-1 plays an important role as an antiapoptotic molecule in BCR/ABL-transformed cells.
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. To investigate the role of HO-1 as a survival-promoting factor in CML cells in the context of BCR/ABL, primary CML cells were treated with the BCR/ABL tyrosine kinase inhibitor STI571 (1 µM) in the presence or absence of hemin (20 µM). As expected, STI571 reduced the viability of CML cells in a time-dependent manner (Fig. 6B)
. However, induction of HO-1 by hemin was found to protect these cells from STI571-dependent cell death (Fig. 6B)
. Moreover, treatment with hemin was found to counteract STI571-induced apoptosis in these cells (Fig. 6C)
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. Simultaneous exposure to CO, biliverdin, and DFX did not further enhance survival of STI571-treated K562 cells compared with the combinations CO plus DFX or CO plus biliverdin (Fig. 7)
. Together, these data suggest that heme degradation products may play a role in HO-1-mediated survival of CML cells. However, because we could not mimic the effect of hemin by applying CO, biliverdin, and DFX, it seems likely that other mechanisms are also involved in the survival-promoting function of HO-1 in CML cells.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The observation that leukemic cells in patients with CML express HO-1 in a constitutive manner is a remarkable finding that is consistent with expression of HO-1 in solid tumors (20, 21, 22, 23) . By contrast, most normal cells and tissues are considered to express only low amounts of (or to lack) HO-1 unless exposed to certain (stress inducing) stimuli (13) . On the basis of this notion, we were interested to know whether the disease-related oncoprotein BCR/ABL plays a role in the constitutive expression of HO-1 in CML cells. Supporting this hypothesis, the BCR/ABL tyrosine kinase inhibitor STI571 was found to down-regulate expression of HO-1 in primary CML cells. Moreover, we found that BCR/ABL induces expression of HO-1 in Ba/F3 cells. To the best of our knowledge, this is the first study showing that a leukemia-related oncogene promotes HO-1 gene expression. Whether HO-1 is also expressed in other leukemias and/or nonhematopoietic malignancies in an oncogene-dependent manner remains at present unknown. In this regard, it is of interest that also oncogenic Ras was found to induce HO-1 gene expression in Ba/F3 cells.3 Thus, it may be tempting to speculate that oncogene-dependent expression of HO-1 is a more general phenomenon that may occur in various (myeloid) neoplasms.
A number of recent studies have implicated HO-1 as an antiapo-ptotic effector molecule in mesenchymal cells exposed to oxidative stress (15 , 19) . To address the question as to whether HO-1 also acts as a survival factor in leukemic cells, HO-1 was overexpressed in BCR/ABL-transformed cells by two independent approaches. In a first step, K562 and Ba/F3 cells were exposed to hemin, resulting in up-regulation of HO-1. These hemin-exposed (HO-1 overexpressing) cells were found to be far less susceptible to STI571-dependent cell killing compared with CO cells. To directly show that HO-1 exerts a protective effect against STI571, K562 cells were transiently transfected with the HO-1 cDNA, and again, HO-1 was found to counteract STI571-induced apoptosis in K562 cells.
The above observations prompted us to ask whether HO-1 can be used as a novel molecular target in primary CML cells. To address this issue, a specific inhibitor of HO-1, ZnDPPIX (30) , was applied and found to decrease cell viability and increase apoptosis in primary CML cells. In this regard, it is of interest, that a water-soluble pegylated zinc protoporphyrin (PEG-ZnPP) has recently been developed and found to act as an antineoplastic agent in experimental solid tumors in vivo (33) . Whether a similar approach can be developed far enough in leukemias to enter clinical trials in the future remains at present unknown. Likewise, it may be of interest to test whether HO-1 expression plays a functional role in STI571-resistant CML cells and whether combination therapy using STI571 and a HO-1-targeting drug would counteract the development or overcome resistance against STI571.
A number of studies have shown that HO-1 exerts antiapoptotic effects through generation of heme degradation products, including biliverdin, iron, and CO (19
, 23
, 32)
. We therefore asked whether these degradation products are involved in HO-1-dependent survival of CML cells. The results of our study show that various combinations of biliverdin, CO, and DFX counteract STI571-induced cell death in CML cells. However, no significant effect was seen when these substances were applied as single agents. Moreover, even when used in combination, the STI571-induced apoptosis could only in part be reverted by these compounds contrasting their effects on endothelial cells and fibroblasts (15
, 16)
. This discrepancy may have several explanations. A reasonable explanation would be that additional HO-1-dependent mechanisms (apart from CO, biliverdin, and iron) play a role in cell survival in CML cells. Thus, the mechanisms underlying HO-1-induced survival in neoplastic (leukemic) cells may differ from that contributing to HO-1-dependent survival in non-neoplastic cells. Another reason for the different effects of CO, biliverdin, and DFX in CML cells as opposed to other cell types may be the different stimuli used to induce apoptosis. The possibility that the divergent result was caused by differences in the methodology applied (i.e., in CO exposure) could be excluded by the demonstration that CO inhibited the lipopolysaccharide-induced production of tumor necrosis factor-
in RAW 264.7 mouse macrophage cells in the same way as described by Otterbein et al. (Ref. 29
; data not shown).
In summary, our data show that primary CML cells express HO-1 in a constitutive manner and that expression of this gene is associated with increased survival of leukemic cells. Moreover, our data show that targeting of HO-1 in CML cells is associated with reduced survival and increase in apoptosis. Whether these observations will have clinical implications in the future remains at present unknown.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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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.
Requests for reprints: Christian Sillaber, Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, AKH-Wien, Währinger Gürtel 18-20, A-1097 Vienna, Austria. Phone: 43-1-40400-6085; Fax: 43-1-402-6930; E-mail: christian.sillaber{at}univie.ac.at
Received 5/ 1/03. Revised 1/21/04. Accepted 2/25/04.
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