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Experimental Therapeutics, Molecular Targets, and Chemical Biology |
, Causing Glycolysis Shutdown and Cell Death
1 Department of Neurobiochemistry, George S. Wise Faculty of Life Sciences and 2 Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel and 3 Department of Pediatric Hematology-Oncology, Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel
Requests for reprints: Yoel Kloog, Department of Neurobiochemistry, George S. Wise Faculty of Life Sciences, Tel-Aviv University, 69978 Tel-Aviv, Israel. Phone: 972-3-640-9699; Fax: 972-3-640-7643; E-mail: yoelk{at}tauex.tau.ac.il.
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Abstract |
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(HIF-1) disappeared, expression of key glycolysis pathway enzymes and of other HIF-1–regulated genes (including vascular endothelial growth factor and the Glut-1 glucose transporter) was down-regulated, and glycolysis was halted. This led to a dramatic reduction in ATP, resulting in a severe energy crisis. In addition, the expression of E2F-regulated genes was down-regulated in the FTS-treated cells. Consequently, U87 cell growth was arrested and the cells died. These results show that FTS is a potent down-regulator of HIF-1 and might therefore block invasiveness, survival, and angiogenesis in GBM.
Key Words: Ras • hypoxia-inducible factor-1 • glioblastoma • Ras inhibitors • FTS
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Introduction |
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Cell culture experiments with glioma cell lines have provided persuasive evidence that various RTKs activate several common pathways and, in particular, those that lead to activation of Akt and Ras. Receptor-mediated Ras activation, which facilitates exchange of GDP for GTP (10), and Ras activation by oncogenic mutation are common in human tumors and contribute to the development and maintenance of the malignant phenotype (11). For example, the active Ras-GTP protein, through its downstream effectors including Raf, PI3-K, and Ral-guanine nucleotide exchange factors, promotes cell cycle progression, survival, and migration (10, 12) . Although oncogenic mutations that affect Ras are not prevalent in human gliomas, recent studies revealed the abundant presence of Ras-GTP in these tumors (13). Thus, receptor-mediated activation of Ras signaling might be required for the induction, progression, and maintenance of gliomas. Consistent with this suggestion, expression of dominant-negative Ras in the glioma cell line U373 results in inhibition of Ras signaling to the Raf/MEK/ERK and attenuation of cell growth (13). Attempts have been made to block Ras or Ras-dependent functions in GBM cells using farnesyl transferase inhibitors (14). However, knowledge of the direct effect of Ras inhibitors on human GBM cells is still limited. In the present study, we used the potent Ras inhibitor S-trans, trans-farnesylthiosalicylic acid (FTS), which affects directly the membrane-bound Ras protein (15). Our results show that FTS induces growth arrest and cell death in U87 GBM.
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Materials and Methods |
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(HIF-1) antibody was from BD Transduction Laboratories (San Jose, CA); peroxidase-goat antimouse immunoglobulin G, peroxidase-goat antirabbit immunoglobulin G and peroxidase-donkey anti-goat immunoglobulin G were from Jackson ImmunoResearch Laboratories (West Grove, PA); anti-VEGF antibody was a gift from G. Neufeld (Technion, Haifa, Israel); rabbit anti-PFKFB4 was from Abgent (San Diego, CA); goat anti–lactate dehydrogenase antibody was from abcam (Cancun, Mexico). Carbobenzoxy-L-leucyl-L-leucinalZ-LLL-CHO (MG132) was from Calbiochem (La Jolla, CA). Cell Culture and Cell Proliferation Assays. Cells were grown at 37°C in DMEM containing 5% FCS, 100 µg/mL streptomycin, and 100 units/mL penicillin and maintained in a humidified atmosphere of 95% air/5% CO2 (normoxia) or of low oxygen pressure (1% O2) where indicated. Cells were plated at a density of 5,000 cells per well in 24-well plates for direct cell-count assays, in 96-well plates for cell-proliferation assays [bromodeoxyuridine (BrdUrd) labeling and detection kit III, Roche Molecular Biochemicals, Mannheim, Germany], or at a density of 1.5 x 106 cells in 10-cm dishes for all other assays including fluorescence-activated cell-sorting (FACS) analysis of propidium iodide (BDH, Poole, United Kingdom)–stained cells. The cells were treated 24 hours after plating or 12 hours after serum starvation, with different concentrations of FTS or with the vehicle (0.1% DMSO). All assays were done in triplicate or quadruplicate. Data were expressed as means ±SD. Statistical significance was determined by an unpaired Student's t test.
Immunoblotting, Ras-GTP, and PI3-K Assays. To determine the effects of FTS on Ras and its downstream signals on HIF-1, VEGF, aldolase c, lactate dehydrogenase, and PFKFB4 we used lysates of cells pretreated with 70 µmol/L FTS for 24 hours as described above and did Western immunoblotting analysis or Ras-GTP and PI3-K assays (17). Protein bands were visualized by enhanced chemiluminescence (ECL, Amersham Biosciences AB, Buckinghamshire, United Kingdom) and quantified as detailed (17). Ras-GTP was determined by the glutathione S-transferase-Ras binding domain of Raf (RBD) pull-down assay as previously described (17). PI3-K activity was determined essentially as detailed earlier (17). All biochemical and immunoblotting assays were repeated at least thrice. Data are presented as means ± SD.
Immunocytochemistry. U87 glioblastoma cells were cultured to approximately 80% confluence on glass coverslips in six-well plates and incubated with 70 µmol/L FTS or the vehicle (0.1% DMSO) for 48 hours in hypoxic conditions (1% O2). The cells were fixed, permeabilized, and labeled with HIF-1 antibody and Red Cy3–conjugated donkey anti-mouse as detailed earlier (18). The cells were then imaged with a fluorescence microscope IX70 (Olympus America, Inc., Melville, NY) with a 1.40 numerical aperture, 63x objective, and Cy3 filter set, using the 4.0.4 SpotAdvanced imaging software.
Measurements of pH and ATP. The pH of the culture medium and the free ATP in the cells was measured to assess the effects of FTS on the end products of glycolysis. U87 cells (triplicate samples) were treated with 70 µmol/L FTS or with the vehicle (0.1% DMSO), as described above, for the indicated periods. Media were collected and the pH was immediately determined. A constant light signal luciferase assay (ATP bioluminescence assay kit CLSII, Boehringer Mannheim Biochemicals, Mannheim, Germany) was used to determine the cellular content of free ATP according to the manufacturer's instructions.
Gene Expression Profiling. All experiments were done using Affymetrix Human Genome Focus oligonucleotide arrays (Santa Clara, CA). The effect of FTS on gene expression in U87 cells was determined 24 and 48 hours after treatment with FTS (70 µmol/L) or vehicle (a single microarray for each condition). Zero time incubation was included. Total RNA from each sample was used to prepare biotinylated target RNA that was used to generate cRNA as detailed http://bioinf.picr.man.ac.uk/mbcf/downloads/GeneChip_Target_Prep_Protocol-CR-UK_v3.pdf). Spike controls were added to 15 µg of fragmented cRNA before overnight hybridization. Arrays were then processed and scanned on an Affymetrix GeneChip scanner as detailed at the above Web site. The quality and amount of total RNA were analyzed using an agarose gel. After scanning, array images were assessed visually to confirm scanner alignment and the absence of significant bubbles or scratches on the chip surface. Ratios of 3'/5' for glyceraldehyde-3-phosphate dehydrogenase and ß-actin were confirmed to be within acceptable limits (0.91-1.13 and 0.95-1.39, respectively) and BioB spike controls were found to be present on all the arrays, with BioC, BioD, and CreX also present with increasing intensity. When scaled to a target intensity of 150 (using Affymetrix Microarray Suite 5.0 array analysis software), scaling factors for all arrays were found to be within acceptable limits (0.56-1.2), as were the background, Q values, and mean intensities. Details of quality control measures are recorded in the supplement (see quality control table in http://eng.sheba.co.il/genomics).
Analysis of Gene Expression Data. Genes were analyzed using the MAS 5 algorithm (see pivot data in supplement http://eng.sheba.co.il/genomics). A list of 5,054 probe sets, or "valid genes," was obtained, representing probe sets with signals higher than 20 and detected as present in at least one sample (see valid genes in http://eng.sheba.co.il/genomics). A comparison of FTS-treated cell samples with untreated cell samples yielded a list of 1,212 "active genes" (see active genes in http://eng.sheba.co.il/genomics), representing genes whose expression was increased by at least 2-fold (log ratio 
1), detected as an "increase" or a "marginal increase", or genes whose expression was decreased by at least 2-fold (log ratio 
–1), detected as a "decrease" or a "marginal decrease" at least at one time point. Hierarchical clustering was done using Eisen clustering and visualization tools (ref. 19; http://rana.lbl.gov/EisenSoftware.htm). Genes were classified into functional groups using the GO annotation tool (ref. 20; http://apps1.niaid.nih.gov/David/upload.asp). Overabundance was calculated using EASE software (21). Functional classifications with an EASE score lower than 0.05 were marked as overabundant.
Real-time PCR analysis. Extracts of total RNA (1 µg) from cells treated for 48 hours with FTS (70 µmol/L) or vehicle (control) were reverse-transcribed in a total volume of 20 µL using the iSCRIPT cDNA kit (Bio-Rad). The cDNA samples were then used for real-time PCR (Syber Green PCR kit, Roche). The PCR conditions and the primers used for PFKFB3, Glut-1 (SLC2A1), PDGFRA, and VEGFC genes and for the housekeeping genes GAPDH and HMBS are detailed in the supplement (Real-time PCR Table, http://eng.sheba.co.il/genomics).
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Results |
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Next we examined the effect of FTS on U87 cell proliferation. Serum-stimulated BrdUrd incorporation into DNA was inhibited by FTS, with 50% inhibition occurring at 70 µmol/L FTS (Fig. 2A). Counting of cells grown for 5 days in the presence of FTS showed that the drug induced a dose-dependent decrease in cell number (with 50% decrease at 50 µM FTS; Fig. 2B). This decrease was attributable not only to inhibition of proliferation; FACS analysis carried out 48 hours after FTS treatment showed that the drug induced a time-dependent increase in the sub-G1 cell population (Fig. 2C) indicating that the observed decrease in cell number is in part a reflection of cell death (51% of the cells were not viable after 48 hours of FTS treatment). This finding suggests that the Ras inhibitor affected a multitude of Ras-dependent pathways that control cell growth and cell death or survival.
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0.00217) and in the group of genes that are involved in metabolism (P 0.0000903) were overabundant in the FTS-treated cells. Analysis of genes in the category of cell growth indicated dramatic changes in the expression of enzymes that participate in cell cycle, cell cycle arrest, cell cycle checkpoint, cell differentiation, cell proliferation, chromatin modification, DNA metabolism, DNA repair, and mitotic pathways (see valid genes in supplement, http://eng.sheba.co.il/genomics). Thus, for example, we observed a decrease in expression of the following genes (the fold decrease in each case is given in parentheses): cyclin E2 (4.6), cyclin A2 (7.5), cyclin B2 (6.5), Orc1L (19.7), Mcm5 (9.2), CDC2 (24), and POLE (8). Although these results need to be validated, they clearly are consistent with the observed FTS-induced inhibition of U87 cell proliferation (Fig. 2A and B). In addition, they are in accord with the known regulation of the cell cycle by active Ras and Ras-dependent pathways (22).
FTS Decreases the Expression of Genes Regulated by HIF-1. Examination of the FTS-induced alterations in genes that participate in metabolism suggested that 12 genes of the ubiquitously expressed glycolytic pathway were transcriptionally down-regulated by FTS (see mRNA hybridization intensity, Fig. 4A). The fold decreases in the expression of genes encoding the relevant enzymes, relative to control, are indicated in Fig. 4B. The decrease was most prominent in phosphofructokinase (PFKFB4 and PFKFB3), the rate-limiting glycolytic enzyme. Real-time PCR analysis showed that FTS reduced the expression of the PFKFB3 gene by a factor of 2.7 ± 0.006. The above-mentioned decrease in the expression of genes of the glycolytic pathway was also manifested at the protein level. This is shown by the observed decrease in the amounts of three key glycolytic enzymes (Fig. 5A).
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(23, 24) it seemed reasonable to assume that FTS affected HIF-1, even though the gene-profiling data did not indicate a significant decrease in HIF-1 gene expression. This latter finding was expected, because HIF-1 protein levels are controlled mainly via posttranslational degradation. Consistent with this possibility, we found that the expression of more than 20 other genes controlled by HIF-1 was down-regulated by FTS (see Table 1). Notably, this list includes the genes encoding VEGFC (25), transforming growth factor , and PDGFRA (important for GBM cell motility; ref. 26), DEC-1 (important for adaptation to hypoxia, ref. 27), and the major glucose transporter Glut-1 (28). Real-time PCR validated the FTS-induced decrease in the expression of Glut-1 (6.5 ± 0.017), PDGFRA (11.5 ± 0.007), and VEGFC (3.0 ± 0.03). In addition, immunoblotting analysis with anti-VEGF antibody showed that VEGF protein was down-regulated as well (Fig. 5A).
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Protein with Resulting Blockage of Glycolysis. Next, we examined by immunoblotting the effect of FTS on the cellular levels of HIF-1 protein. U87 cells were grown in the presence or absence of 70 µmol/L FTS for various periods under hypoxia (1%), a condition that stabilizes HIF-1 (29). We found that FTS induced a dramatic decrease in HIF-1 within 24 hours (Fig. 5B). After 48 hours or 72 hours of treatment HIF-1 was almost undetectable, with levels lower than 5% of controls (P < 0.005). Similar results were obtained with three other GBM cell lines, namely, U373, 20/20, and LN229 (Fig. 5C). Immunofluorescence analysis confirmed these results; FTS treatment caused a complete disappearance of HIF-1 from the U87cells nuclei with no accumulation of the protein in the cytosol (Fig. 5D). The FTS-induced down-regulation of HIF-1 protein could be associated with a mechanism in which the inhibition of Akt (Fig. 1) promoted proteasomal degradation of HIF-1 as was shown previously (30). Consistent with this possibility we found that the proteasome inhibitor MG132 blocked the FTS-induced disappearance of HIF-1 (Fig. 5E). These results prompted us to examine the effect of the Ras inhibitor on the principal end products of glycolysis. First, we determined the cellular content of ATP. U87 cells were treated with 70 µmol/L FTS and assayed 24, 48, and 72 hours later. All assays were normalized to equal amounts of cellular protein. ATP showed a time-dependent decrease, reaching a level corresponding to 20% of that in control cells at 72 hours (Fig. 6A). Next we determined the acidity of the growth medium, caused primarily by lactate, another glycolytic end product. Treatment with FTS diminished acidity, consistent with inhibition of lactate accumulation (Fig. 6B). Thus, the pH of the medium of the treated cells was significantly higher than that of controls (Fig. 6B). It should be noted that the time-dependent reduction in pH of the control cells did not result from the presence of more cells. Under the experimental conditions used and at the time points of measurement, cell numbers in the FTS-treated and control preparations were similar.
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Discussion |
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protein disappeared (Fig. 5), expression of key enzymes of the glycolysis pathway was down-regulated (Fig. 4), and glycolysis was halted (Fig. 6). This led to a severe energy crisis in which ATP was dramatically reduced (Fig. 6). In addition, expression of E2F-regulated genes, required for cell cycle progression, was down-regulated in the FTS-treated cells (Fig. 3). Consequently, U87 cell growth was arrested and the cells died (Fig. 2).
Our data are consistent with the notion that the major effects of FTS result from blocking of Ras activation. First, it is well documented that active Ras, operating via the Raf/MEK/ERK and the PI3-K/Akt/GSK-3 pathways, regulates the amounts of cyclin D1 and of CDK4/cyclin D1 assembly, leading to an increase in E2F transcriptional activity and enhanced cell proliferation (22). Indeed, we found that FTS induced a decrease in E2F-regulated genes. The apparent decreases observed in the expression of E2F-regulated genes, such as cyclin E2 and CDC2, provide an explanation for the FTS-induced inhibition of U87 cell growth. Second, studies have shown that the level and activity of HIF-1 protein are controlled by Ras (33). Ras regulates the stability and transcriptional activity of HIF-1 (33) by mechanisms that involve, respectively, GSK-3-dependent and ERK-dependent phosphorylation of the transcription factor (30). Our present finding that FTS inhibited ERK and Akt activation (Fig. 1) is consistent with the notion that Ras inhibition by FTS leads to inhibition of Ras signaling and destabilization of HIF-1 protein.
The strong association between Ras-HIF-1 and tumorigenicity is well documented. For example, active Ras increases HIF-1 expression in breast cancer cells (33), whereas expression of HIF-1 is blocked by a PI3-K inhibitor in prostate cancer cells (34) and in Ras-transformed NIH3T3 cells (35). Inhibition of ERK in HepG2 cells (36) and in colon cancer cells (37) resulted in blocking of HIF-1 activation or expression. In another study with NIH3T3 cells, ERK was shown to enhance HIF-1 transcriptional activity, whereas Akt was shown to stabilize HIF-1 protein (30). In addition, expression of a dominant-negative form of PI3-K or expression of PTEN resulted in a decrease in HIF-1 activity in U373 GBM cells (38). Related studies showed strong expression of HIF-1 in human gliomas (3, 39, 40) that exhibit high Ras-GTP levels and in pancreatic tumor cell lines (41) that harbor oncogenic Ras and/or overexpress EGFR (42). Our present results show that a reduction in active Ras in GBM (Fig. 1) is accompanied by a dramatic decrease in HIF-1 protein (Fig. 5). The proteasome inhibitor MG132 blocked the disappearance of HIF-1 in FTS-treated GBM cells. Thus, it seems that the decrease in HIF-1 is a result of enhanced degradation of the protein via the known mechanism of proteasomal HIF-1 degradation (43).
In this study we focused on the highly significant FTS-induced changes observed in HIF-1-regulated genes in light of the critical role that this factor plays in maintenance of the malignant phenotype of GBM (3, 39, 40). HIF-1 regulates the expression of many enzymes that participate in glycolysis, a major energy pathway in GBM and in many other types of human tumors (44). We found that 12 genes of the glycolytic pathway (23, 24) were transcriptionally down-regulated by FTS in U87 cells (Fig. 4). This can explain the observed decrease in ATP production. The FTS-induced decrease in expression of both glycolytic enzymes and Glut-1 suggests not only that glycolysis was halted but also that glucose uptake was blocked.
We cannot tell from our experiments whether the FTS-induced death of U87 cells was attributable to the general energy crisis or to both the reduction in ATP and the activation of specific cell-death pathways. It was recently shown that down-regulation of HIF-1 by phosphorothioate antisense HIF-1 oligonucleotide causes apoptotic cell death in U87 cells (45). That study showed that the cytotoxic effect of the antisense HIF-1 was independent of p53 but could be attenuated by caspase inhibitors. We have not yet examined the effects of FTS on the apoptotic machinery in U87 cells, although we know that in other cells, for example, in rat intestinal epithelial cells, FTS promotes anoikis by a caspase-3-dependent mechanism (46). Thus, the observed FTS-induced decrease in HIF-1 protein in GBM cell lines and, taken together with the results of the above-mentioned study (45), suggest the possibility that FTS induces apoptotic cell death in U87 cells. Additional studies are required to resolve this question.
Finally, many studies have now pointed to HIF-1 as an important target for anticancer drugs. Our results provide evidence for the existence of a potent new down-regulator of HIF-1, namely, the Ras inhibitor FTS. Additional studies are needed to determine whether this inhibitor is capable of blocking in vivo the HIF-1-dependent invasiveness, survival, and angiogenesis of GBM.
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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.
We thank the Arison-Dorsman family, Tel-Aviv, Israel, for their donation of DNA chips to Pediatric Oncology, Chaim Sheba Medical Center, and S.R. Smith for editorial assistance.
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Footnotes |
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Supplementary data for this available at Cancer Research Online (http://cancerres.aacrjournals.org).
Received 8/19/04. Revised 11/ 8/04. Accepted 11/19/04.
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References |
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