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Gene expression profiles of proliferating vs. G1/G0 arrested human leukemia cells suggest a mechanism for glucocorticoid-induced apoptosis

MARTIN TONKO^*,, MICHAEL J. AUSSERLECHNER^*, DAVID BERNHARD^*, ARNO HELMBERG^* and REINHARD KOFLER^*,1

^* Institute of General and Experimental Pathology, Division of Molecular Pathophysiology, University of Innsbruck, A-6020 Innsbruck, Austria; and
Tyrolean Cancer Research Institute, Innsbruck, Innrain 66, A-6020 Innsbruck, Austria

¹Correspondence: Tyrolean Cancer Research Institute, Innrain 66, 6020 Innsbruck, Austria. E-mail: Reinhard.Kofler{at}uibk.ac.at

	ABSTRACT

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Glucocorticoids (GC) have pronounced effects on metabolism, differentiation, proliferation, and cell survival (1) . In certain lymphocytes and lymphocyte-related malignancies, GC inhibit proliferation and induce apoptotic cell death, which has led to their extensive use in the therapy of malignant lymphoproliferative disorders (2) . Most of these effects result from regulation of gene expression via the GC receptor (GR), a ligand-activated transcription factor (3) . Although hundreds of genes are regulated by GC (1) , how certain biological GC effects relate to individual gene regulation remains enigmatic. To address this question with respect to GC-induced cell cycle arrest and apoptosis, we applied DNA chip technology (4 , 5) to determine gene expression profiles in proliferating and G1/G0-arrested (by conditional expression of the CDK inhibitor p16/INK4a) acute lymphoblastic T cells undergoing GC-induced apoptosis. Of 7074 genes tested, 163 were found to be regulated by dexamethasone in the first 8 h in proliferating cells and 66 genes in G1/G0-arrested cells. An almost nonoverlapping set of genes (i.e., only eight genes) was coordinately regulated in proliferating and arrested cells. Analysis of the regulated genes supports the concept that GC-induced apoptosis results from positive GR autoregulation entailing persistent down-regulation of metabolic pathways critical for survival.—Tonko, M., Ausserlechner, M. J., Bernhard, D., Helmberg, A., Kofler, R. Gene expression profiles of proliferating vs. G1/G0 arrested human leukemia cells suggest a mechanism for glucocorticoid-induced apoptosis.

Key Words: glucocorticoid-induced gene regulation • DNA chip expression profiling • acute lymphoid leukemia • pathophysiology

	INTRODUCTION

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TO IDENTIFY GLUCOCORTICOID (GC) -REGULATED genes involved in GC-induced inhibition of cell cycle progression and apoptosis, we used the CCRF-CEM acute lymphoblastic T cell leukemia model (6) . GC-treated CCRF-CEM cells undergo cell cycle arrest after 24–36 h, followed by apoptosis starting at 36 h and being complete at 72 h (7 , 8) . When such cells are arrested in G1/G0 by conditional expression of the cyclin-dependent kinase (CDK) inhibitor p16/INK4a, they are still sensitive (in fact, considerably more sensitive [9]) to GC. We reasoned that the expression profile alteration induced by GC in arrested cells might differ from that in proliferating cells. Since both populations undergo apoptosis, we assumed that commonly regulated genes more likely relate to cell death, thereby narrowing down the number of candidate genes for functional analysis. Following this rationale, we prepared mRNA from proliferating and G1/G0-arrested CCRF-CEM derivatives that were either untreated or exposed to 10^-7 M dexamethasone for 2 or 8 h. The effect of GC on cell cycle progression and survival followed the above-mentioned and previously published (7 , 8) kinetics (data not shown). The mRNAs were reverse-transcribed into red and green fluorescent cDNA probes and hybridized pairwise to DNA chips containing 7074 genes (Incyte Genomics, Inc., St. Louis, Mo.). Untreated G1/G0-arrested cells (CEM-C7H2–6E2-p16) [9] were compared with either 2 or 8 h treated G1/G0-arrested cells, and untreated proliferating cells (CEM-C7H2) with their counterparts exposed to dexamethasone for 2 or 8 h.

	MATERIALS AND METHODS

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Cell culture and reagents
CCRF-CEM-C7H2 (8) and CCRF-CEM-C7H2–6E2-p16 [9] cells were maintained in RPMI 1640 containing 10% fetal calf serum (Gibco BRL, Paisley, U.K.), 100 U/ml penicillin, 100 µg/ml streptomycin, and 2 mM L-glutamine (Gibco BRL) at 5% CO₂ at 37°C in saturated humidity. All reagents (dexamethasone, doxycycline) were from Sigma (Vienna, Austria). Proliferating CEM-C7H2 cells were treated with 10^-7 M dexamethasone and probes were removed for mRNA preparation after 0, 2, and 8 h treatments. From the same cells, probes were taken at 0, 24, 48, and 72 h for FACS analyses to check cell cycle and extent of apoptosis in the respective cells. The same procedure was used for CEM-C7H2–6E2-p16 cells, except that these cells were arrested in G1/G0 by 24 h doxycycline treatment (200 ng/ml) before adding dexamethasone. In the concentration used, doxycycline has no detectable effect on cell cycle progression or apoptosis (9 , 10 , 11) . G1/G0 arrest was checked by FACS analysis.

Apoptosis and cell cycle analyses
Nuclear staining with propidium iodide in concert with forward/sideward scatter analysis was used for detection and analysis of cell cycle phase and apoptosis (12 , 13) . Briefly, cells were centrifuged and pellets were resuspended in 0.75 ml hypotonic propidium iodide solution. The tubes were kept at 4°C in the dark overnight. Nuclear fluorescence and forward/sideward scatter were analyzed with a Becton Dickinson FACScan.

Chip analysis
Total RNA was extracted with TriReagent^TM (LPS, Moonachie, N.J.). From this, mRNA was extracted using Quiagen Oligotex^TM columns (Valencia, Calif.). 600 ng mRNA (50 ng/µl) was sent on dry ice to Incyte Genomics, who performed mRNA labeling, hybridizations and primary data preparation. Analyses of the resulting image and data files were performed in our lab using conventional data analysis programs.

Northern blotting
Total RNA was extracted with TriReagent^TM (LPS) from 5 x 10⁶ cells. Eight µg of RNA were separated by electrophoresis on a denaturing 1% agarose gel containing formaldehyde in 4-morpholinopropanesulfonic acid buffer, and blotted overnight onto Zetabind^TM nylon membranes (Cuno, Meridien, Colo.) according to standard protocols. RNA was cross-linked to membranes by UV. Filters were prehybridized in phosphate-blocking buffer containing sodium dodecyl sulfate and bovine serum albumin at 65°C for 3 h, and hybridized for another 12 h to the respective heat-denatured probes. The probes were labeled with -³²P dATP using a Promega (Madison, Wis.) random priming DNA labeling kit. Northern-probes were derived from clones purchased by Incyte Genomics.

	RESULTS

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The complete expression profiles can be accessed through the internet (www. tilak.or.at/tkfi). In Table 1 ,we provide a summary of all genes whose regulation was considered significant ( twofold, as recommended by Incyte Genomics). Using this criterion, 163 genes were regulated by dexamethasone in proliferating cells and 66 genes in G1/G0-arrested cells. However, only eight genes were coordinately regulated both in proliferating and arrested cells (Table 2 ).

To test the reliability of the above data, we confirmed the regulation of some individual genes by Northern blot experiments. As shown in Fig. 1 , all such tests (i.e., LDH, leucine zipper, EphB6, glucan-1,4-branching enzyme, squalene synthase) confirmed the results of the DNA chip analysis-derived data. To test the data validity as a whole, we compared our data with reports on GC-regulated genes in the literature. Whereas our previous analysis recorded 225 GC-regulated genes in 1996 (1) , our recent PubMed search resulted in 363 GC-regulated genes, 220 of which could be unambiguously assigned to genes present on the chip (see www.tilak.or.at/tkfi). 12% (26 genes) were clearly regulated by chip criteria ( twofold); an additional 29% (64 genes) showed evidence for regulation (1.6- to 1.9-fold regulation). Since the data on GC-regulated genes in the literature derived from multiple tissues, species, and conditions, the observed congruence is remarkable and, although not allowing conclusions for any individual regulation, strongly supports the validity of the data set as a whole.

View larger version (24K): [in this window] [in a new window]   Figure 1. Chip images and corresponding Northern blots of GC-regulated genes. Shown are the leucine zipper (LZ, top panel) (20) , LDH-A (second panel) (17) , EphB6 (third panel) (21) , glucan-1,4-branching enzyme (Gluc 1,4 BE, fourth panel), and squalene synthase (SS, bottom panel) as chip spots and respective Northern bands (untreated: 0 and 8 h GC treated; see also Table 1 ). C7H2 reflects proliferating cells; 6E2(+p16/G1) reflects cells arrested in G1 by conditional expression of p16/INK4a. As loading control, ethidium bromide (EtBr) stained 28S rRNA bands are shown.

	DISCUSSION

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When relating the above expression profile changes to GC-induced cell cycle arrest and apoptosis, we were struck by the observation that the GC receptor (GR) was among the very few genes regulated in both proliferating and G1/G0-arrested cells. Its marked up-regulation was particularly stunning, because GC down-regulate their receptors in most tissues investigated (14) . Supporting our data, GC up-regulation was observed and implicated in GC-induced cell death many years ago (15) , and its significance for GC-induced leukemia apoptosis was suggested recently in elegant experiments (16) . Assuming that GR up-regulation (or lack of down-regulation) is a critical prerequisite for cell death, we propose that the subsequent continuous repression of various metabolic pathways (Fig. 2 ) might have a role in cell cycle arrest and ultimately lead to cell death. Particularly critical in this regard might be the down-regulation of the lactate dehydrogenase (LDH) gene seen in proliferating and G1/G0-arrested cells. This enzyme controls glycolysis in cancer cells (17 , 18) , a pathway preferentially used by (and perhaps critical for) malignant cells to generate ATP, as originally reported in 1926 by Otto Warburg (‘Warburg effect’) (19) . Given that our analysis covered only 10% of the genes in the human genome, other pathways controlled by genes not on the chip may also be affected. Obviously, this concept needs to be tested in additional cell lines and, most important, in cells from afflicted patients treated with GC in vivo, a subject currently under investigation in our laboratory. Moreover, details of the proposed ‘metabolic disaster’ need to be delineated as well as the question of whether GC-induced apoptosis follows the same mechanistic principle in malignant and normal, and proliferating and arrested lymphocytes.

View larger version (26K): [in this window] [in a new window]   Figure 2. Overview of metabolic pathways affected by GC treatment. GC regulate mRNAs for enzymes important in glycolysis: hexokinase 1 [1] (AF016365); glucan-1,4-branching enzyme [2] (L07956); fructose-1,6-bisphosphatase [3] (U21931); aldolase A [4] (M11560); triosephosphate isomerase [5] (U47924); phospho-glycerate kinase 1 [6] (V00572); lactate dehydrogenase A [8] (LDH, X02152); amino acid biosynthesis: 3-P-glycerate-dehydrogenase [7] (AF006043); malic enzyme 2 [9] (M55905); cholesterol: ATP citrate lyase [10] (X64330); Hydroxymethylglutaryl (HMG) CoA-reductase (11) (M11058); squalene synthase [12] (X69141); steroid biosynthesis: arylsulfatase [13] (M16505); and Inositol monophosphate (IMP) production: ADE2 [14] (X53793). mRNAs for all mentioned enzymes are down-regulated by GC except for fructose-1,6-bisphosphatase [3] and malic enzyme 2 [9] which are up-regulated. As can be seen in Tables 1 and 2 , only lactate dehydrogenase A [8] and arylsulfatase [13] are regulated in cycling and in arrested cells. HMG CoA reductase [11] was previously described by us and others to be regulated by GC (22 , 23) , and shows a tendency to be regulated on the chip (see www.tilak.or.at/tkfi). Dotted arrows indicate additional regulatory steps in between, normal arrows indicate direct reactions; double arrows symbolize reactions possible in both directions.

In conclusion, our data provide for the first time a comprehensive insight into the complex network of GC-regulated genes in human leukemia cells and suggest a testable hypothesis for the mechanism of GC-induced apoptosis.

	ACKNOWLEDGMENTS

 
The authors thank S. Geymayer, W. Doppler, and A. Amberger for valuable discussions and critical reading of the manuscript and I. Jaklitsch for technical assistance. This study was supported by grants from the Austrian Science Fund (SFB-F002, P11964-Med, and P11306).

Received for publication May 24, 2000. Revision received September 5, 2000.

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