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Graduate Institute of Physiology (W.-B.Z., W.-S.L.), College of Medicine, National Taiwan University, Taipei 110, Taiwan; Department of Internal Medicine (C.-Y.W.), Far-Eastern Memorial Hospital, Taipei 220, Taiwan; Department of Internal Medicine (C.-Y.W., T.-C.C.), National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei 110, Taiwan; and Graduate Institute of Medical Sciences (W.-S.L.), Taipei Medical University, Taipei 110, Taiwan
Address all correspondence and requests for reprints to: Tien-Chun Chang, M.D., Ph.D., Department of Internal Medicine, National Taiwan University Hospital, College of Medicine, 7, Chung-Shan South Road, Taipei 110, Taiwan. E-mail: tcchang1{at}ms10.hinet.net; or Wen-Sen Lee, Ph.D., Graduate Institute of Medical Sciences, Taipei Medical University, 250 Wu-Hsing Street, Taipei 110, Taiwan. E-mail: wslee{at}tmu.edu.tw.
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Introduction |
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Apoptosis occurs in various physiological and pathological processes, and it could be induced by activation of Fas signal, UV irradiation, certain chemical reagents, and depletion of cytokines or growth factors. The cellular alternations of apoptosis include loss of membrane asymmetry, chromatin condensation, and DNA fragmentation by DNase activated by caspases (6, 7, 8). Caspases are cysteine aspartate proteases synthesized as inactive precursor molecules, which could be converted to active heterodimers by proteolytic cleavage. Once cells undergo apoptosis, activation of initiator caspase can sequentially activate effector caspases to perform the proteolysis of specific cellular protein target such as poly (ADP-ribose) polymerase (PARP) and then lead to elimination of DNA repair function (9). It has been previously reported that apoptosis in thyroid cancer cells can be induced by manumycin A and paclitaxel, 7-hydroxystaurosporine, sodium butyrate and trichostatin A, and amiodarone (10, 11, 12, 13). In addition, lovastatin was also reported to induce apoptosis in papillary thyroid cancer cells (14). Whether lovastatin can trigger the occurrence of apoptosis of anaplastic thyroid cancer cells remains to be determined.
Lovastatin, a 3-OH-3-methyl-glutaryl CoA (HMG-CoA) reductase inhibitor, has been used to treat hypercholesterolemia through blocking the mevalonate biosynthesis pathway. Inhibition of mevalonate synthesis may result in reductions of isoprenoid prenylation, including geranylgeranyl pyrophosphate (GGPP) and farnesyl pyrophosphate (FPP) (15, 16, 17). Prenylation of small GTP-binding proteins, such as Ras superfamily proteins, with farnesyl or geranylgeranyl group, is required for their translocation to the plasma membrane and their functions (18, 19). Translocation of the small GTP-binding proteins is related to cell survival, proliferation, adhesion, differentiation, and invasion (20, 21, 22, 23, 24). These two posttranslational modifications of Ras superfamily are catalyzed by farnesyl transferase (FTase) and type I geranylgeranyl transferase (GGTase I). Protein farnesylation and geranylgeranylation can be selectively inhibited by peptidomimetic inhibitors, FTI-277 and GGTI-298, respectively (25, 26).
It has been reported that lovastatin is able to induce either apoptosis or cell cycle arrest depending on the cell types. For instance, lovastatin-induced cell cycle arrest was observed in colon cancer and glioblastoma cells (27, 28), and the occurrence of apoptosis was seen in medulloblastoma (29) and myeloid leukemia cells (30, 31). Recently we also found that lovastatin could induce differentiation of ARO cells (Wang, C. Y., W. B. Zhong, T. C. Chang, S. M. Lai, and Y. F. Tsai, manuscript submitted). Because both farnesylation of Ras family and geranylgeranylation of Rho family have been reported to be involved in proliferation inhibition and the occurrence of apoptosis in different groups (15, 16, 17), it is important to determine which pathway is responsible for the lovastatin-induced apoptosis. Accordingly, we attempted to delineate the molecular mechanism underlying of the lovastatin-induced apoptosis in human ARO cells.
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Materials and Methods |
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was purchased from Roche Molecular Biochemicals (Vienna, Austria). Y-27632 was purchased from Tocris Cookson Ltd. (Avonmouth, UK). Cycloheximide, actinomycin D, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), mevalonic acid, geranylgeraniol (GGOH), and farnesol (FOH) were purchased from Sigma Chemical Co. (St. Louis, MO). Lovastatin is a gift from Standard Chemical and Pharmacy Co., Ltd. Taiwan.
Cell culture
The human ATC cell line, ARO cells (33), was a gift from Dr. Chen, S.D. (Chang Gung Memorial Hospital, Touyuan, Taiwan). ARO cells were cultured in RPMI 1640 medium supplemented with 5% fetal bovine serum, 100 U/ml penicillin, and 100 µg/ml streptomycin at 37 C with 5% CO2. They were subcultured twice a week and only those in exponential growth phase were used in these experiments.
DNA fragmentation analysis with agarose gel electrophoresis
After treatment with lovastatin, the cells at the indicated time point were harvested and then suspended with lysis buffer containing 20 mM NaCl, 10 mM Tris-HCl (pH 8.0), 25 mM EDTA, 1% sodium dodecyl sulfate, and 1 mg/ml proteinase K for 24 h in a 55 C water bath. Standard phenol/chloroform/isoamyl alcohol method (25:24:1) was used to remove protein and extract nucleic acid. RNA and digested with RNase A (100 µg/ml) for 12 h at 37 C, and DNA concentrations were determined. DNA extracts were electrophoresed on a 2% agarose gel at 50 V for 45 min and visualized with ethidium bromide staining under UV illumination.
Determination of apoptosis by hypodiploid DNA in flow cytometry
Apoptosis was assessed according to the percentage of cells with hypodiploid DNA, using the propidium iodide-staining technique. Briefly, the treated cells were washed in PBS and centrifuged, dispersed in 70% ethanol, and stored overnight at -20 C. On the following day, they were washed with PBS and incubated at 37 C for 30 min with PBS containing 1 mg/ml RNase A (Sigma) and 50 µg/ml propidium iodide (Sigma) at room temperature in the dark for 1 h. The stained cells were detected using a FACSCalibur flow cytometer (Becton Dickinson, San Jose, CA) and analyzed using the CELLQuest software. Apoptotic nuclei were distinguished by their hypodiploid DNA content from the diploid DNA content of normal nuclei.
Western blot analysis
Thirty micrograms of cytoplasmic proteins were electrophoresed on 10% polyacrylamide gels and transferred to nitrocellulose membranes. Immunoblotting was carried out with specific antibodies in PBS with 0.2% Tween 20 (Sigma) and 5% BSA (Sigma). Specific proteins were visualized using the enhanced chemiluminescence method (Amersham Pharmacia Biotech).
Analysis of caspase activity
To study the caspase activation profiles in lovastatin-induced apoptosis, we assayed caspase activity using an assay kit (Promega, Madison, WI). This assay is based on the spectrophotometric detection of the 7-amino-4-methylcoumarin (AMC) after cleavage from the labeled substrates. Cells were harvested in lysis buffer [25 mM HEPES, 1 mM EGTA, 5 mM EDTA, 5 mM MgCl2, 5 mM dithiothreitol (DTT), 0.01% 3-[(3-cholamidopropyl) dimethyl-ammonio]-1-propane-sulfonate, 10 µg/ml pepstatin, 10 µg/ml leupeptin, 1 mM phenylmethylsulfonylfluoride (PMSF), pH 7.4]. Cell lysates were clarified by centrifugation at 10,000 x g for 5 min, and clear lysates containing 50 µg protein were incubated with 25 µM Ac-YVAD-AMC (caspase-1 substrate), Ac-VDVAD-AMC (caspase-2 substrate), Ac-DEVD-AMC (caspase-3 substrate), Ac-IETD-AMC (caspase-8 substrate), or Ac-LEHD-AMC (caspase-9 substrate) at 37 C for 1 h. The released AMC levels were measured using a spectrofluorometer (F-4500, Hitachi, Tokyo, Japan) with excitation at 360 nm and emission at 460 nm.
Cytochrome c release
The release of cytochrome c from the mitochondria to the cytosol during lovastatin-induced apoptosis was examined. Mitochondrial and cytosolic fractions were prepared by resuspending cells in ice-cold buffer A (250 mM sucrose, 20 mM HEPES, 10 mM KCl, 1.5 mM MgCl2, 1 mM EDTA, 1 mM EGTA, 1 mM DTT, 17 mg/ml PMSF, 8 mg/ml aprotinin, and 2 mg/ml leupeptin). After chilled for 30 min on ice, the cells were disrupted by 15 strokes with a glass homogenizer. The homogenate was centrifuged twice to remove unbroken cells and nuclei (750 x g, 10 min, 4 C). The pellet was resuspended in buffer A, which represents the mitochondrial fraction. The supernatant was again centrifuged at 100,000 x g for 60 min. The supernatant from this final centrifugation step represents the cytosolic fraction, which was electrophoresed on 12% SDS-polyacrylamide gels after determination of protein concentrations with Bio-Rad reagents, transferred onto polyvinyl difluoride membrane and then probed with anti-cytochrome c or antiglycerol-3-phosphate dehydrogenase antibody. The membrane was reacted with peroxidase-conjugated secondary antibody and then developed in the enhanced chemiluminescence (Amersham Biosciences, Buckinghamshire, UK).
PARP cleavage
We examined whether lovastatin-treated ARO cells can induce PARP cleavage, which in turn causes apoptosis. After treatment with lovastatin, the cells were lysed in 10 mM HEPES (pH 8.0), 150 mM NaCl, 0.1 mM EDTA, 1% Nonidet P-40, 1 mM DTT, 0.5 mM PMSF, 2.0 µg/ml leupeptin, and 2.0 µg/ml aprotinin and then incubated on ice for 30 min followed by centrifugation for 20 min at 10,000 x g. Protein concentrations were determined using Bio-Rad reagents with standard BSA. The protein extracts from lovastatin-treated ARO cells were electrophoresed, transferred, and then probed with anti-PARP monoclonal antibody.
Separation of particulate and cytosolic fractions
The cells were washed with cold PBS and lysed by freeze-thawing in ice-cold lysis buffer containing 50 mM HEPES (pH 7.5), 50 mM NaCl, 2 mM EDTA, 1 mM MgCl2, 10 mM sodium fluoride, 1 mM DTT, 10 mg/ml leupeptin, 10 mg/ml aprotinin, and centrifuged at 100,000 x g for 30 min at 4 C, and the supernatant was collected as the cytosolic fraction. Pellets were homogenized in the above-mentioned lysis buffer containing 2% Triton X-114 and centrifuged at 1000 x g for 10 min at 4 C. The supernatant was collected as the membrane fraction. The protein concentrations in the cytosolic fraction and the membrane fraction were measured and adjusted to the same concentration and then subjected to immunoblotted with antibodies against pan-Ras (clone F132; Santa Cruz Biotechnology, Inc., Santa Cruz, CA), RhoA (clone 119, Santa Cruz Biotechnology), or Rac1 (clone C-14, Santa Cruz Biotechnology).
MTT assay for cell growth and viability
The viability of ARO cells was evaluated using MTT assay. This assay is based on the cleavage of the tetrazolium salt MTT to a dark blue formazan product by mitochondrial dehydrogenase in viable cells. The absorbance of viable cells was measured in a Spectra Microplate Reader (SLT-Labinstruments, Grödig, Austria) with a test wavelength of 570 nm and a reference wavelength of 630 nm.
Statistical analysis
A t test was used to determine the significance between untreated and treated cells, and P < 0.05 was considered significant.
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Results |
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). We then examined the DNA content frequency histograms. Figure 1B shows representative DNA content frequency histograms from the ARO cells treated with various concentrations of lovastatin for 48 h or 50 µM lovastatin for various times, as indicated. The percentage of the hypodiploid cell (G0/G1 subpopulation, an indicator of apoptosis) was increased in lovastatin-treated ARO cells in a dose- (upper panel) and time-dependent manner (lower panel).
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, both cycloheximide (CHX) and actinomycin D can enhance TNF- or anti-Fas antibody-induced apoptosis in ARO cells, suggesting that the synthesis of cell survival signaling molecules is required for the ARO cells preventing the TNF- or anti-Fas antibody-induced cell death. In contrast, the lovastatin-induced apoptosis in ARO cells was dose-dependently prevented by CHX, but not actinomycin D, treatment (Fig. 2B), suggesting that de novo protein synthesis is required for the lovastatin-induced apoptosis in the ARO cells.
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). The increased Ac-LEHD-AMC cleavage activity also began at 12 h after treatment of lovastatin, stayed at plateau, and then declined at 36 h after treatment.
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, B and C, treatment of the ARO cells with 50 µM lovastatin induced cytochrome c translocation from the mitochondria into cytoplasm fraction at 12 h after lovastatin treatment and degradation of PARP, the substrate for caspase-3, at 24 h after treatment. That was paralleled with the time course of the induction of caspase activities and apoptosis. These results suggested that lovastatin induced activations of caspases-2, -3, and -9 but not caspases-1 and -8.
Lovastatin-induced apoptosis was prevented by GGOH treatment
In the present study, we found that mevalonate could prevent the lovastatin-induced the occurrence of apoptosis in a dose-dependent manner (Fig. 4A), suggesting that inhibition of mevalonate synthesis plays an important role in lovastatin-induced apoptosis. To confirm this hypothesis, we applied GGOH and FOH (downstream metabolites of mevalonate) and examined their effect on the lovastatin-induced apoptosis. As illustrated in Fig. 4B, the GGOH, which is metabolized to GGPP in the cells, at a concentration of 10 µM completely prevented the lovastatin-induced apoptosis in ARO cells. In contrast, the FOH, which is metabolized to FPP in the cells, enhanced the lovastatin-induced apoptosis in ARO cells (Fig. 4C). PARP degradation, an indicator for caspase activation, was also analyzed in cell lysates by Western immunoblotting. Administration of mevalonate or GGOH, but not FOH, prevented PARP degradation (Fig. 4D). Taken together, these findings indicate that inhibition of GGPP synthesis, which is essential for protein geranylgeranylation, occurred in lovastatin-induced apoptosis in ARO cells.
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Inhibitory effect of lovastatin on translocation of Rho family from cytosol to membrane
To investigate whether lovastatin-induced apoptosis was due to exhaustion of intracellular GGPP pool and then blockade of protein geranylgeranylation in ARO, we examined the effect of lovastatin on translocation of small GTP-binding proteins (Ras, RhoA, and Rac1) from cytosol to membrane fraction. Treatment of ARO cells with lovastatin dose-dependently decreased the levels of RhoA and Rac1 protein, but not Ras protein, in the membrane fraction (Fig. 5A). The lovastatin-induced translocation inhibition of the Rho family (RhoA and Rac1) was prevented by treatment with mevalonate and GGOH but not by FOH (Fig. 5B). These results suggest that activation of Rho family might be involved in the lovastatin-induced apoptosis in ARO cells.
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), suggesting that RhoA is important for ARO cell survival. To confirm further, we inhibited the activity of RhoA kinase, a downstream effector of RhoA signaling, and examined the occurrence of apoptosis in ARO cells. As illustrated in Fig. 6B, treatment of ARO cells with a RhoA kinase inhibitor, Y-27632, at a range of concentrations (20–180 µM) for 48 h caused a dose-dependent increase in the percentage of hypodiploid cell, and decrease in cell viability (Fig. 6B). Taken together, these results suggested that RhoA/RhoA kinase is required for ARO cell survival.
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Discussion |
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In the present study, we demonstrated that GGOH, a metabolite of mevalonate, prevented the lovastatin-induced the occurrence of apoptosis in ARO cells, suggesting that protein geranylgeranylation is required for the survival of lovastatin-treated ARO cells (Fig. 4B). However the lovastatin-induced proliferation inhibition in ARO cells can be prevented by treatment with mevalonate but not GGOH (data no shown), suggesting that there are two different signaling pathways involved in mevalonate effect on the lovastatin-induced cell proliferation regulation and cell apoptosis. It has previously been reported that FPP, a metabolite of mevalonate, can have some degree of protection on lovastatin-induced apoptosis, that might be due, at least in part, to the conversion of GGPP from FPP (30, 34, 35). Our explanation for the discrepancy between the previous reports and our data is that FOH can be converted to FPP to exert its effect on Ras farnesylation and regulation of the cell proliferation. FOH itself, on the other hand, can also enhance the lovastatin-induced proapoptotic effect. Our data showed that administration of FOH did not cause cell death in ARO cells because treatment with FOH alone without lovastatin did not change significantly the cell death. It has been reported that FOH and GGOH can trigger apoptosis in various cancer cell lines. GGOH induced apoptosis in human HL-60 cells through activation of caspase-3 (36), whereas FOH induced apoptosis by suppression of phosphatidylcholine synthesis in human lung cancer cells and HL-60 cells (36, 37).
To further examine whether protein geranylgeranylation is required for ARO cell survival, we applied GGTI-298 and FTI-277 (two selective CAAX mimetic inhibitors) to inhibit GGTase and FTase, respectively. Our results showed that in the absence of lovastatin, both GGTI-298 and FTI-277 dose-dependently induced apoptosis in ARO cells, although the FTI-277 showed less effect, compared with GGTI-298. To confirm that the protein farnesylation is also essential in preventing ARO cells from apoptosis, we conducted the same experiment using manumycin A, a FPP competitor, and showed an apoptotic effect in a degree similar to GGTI-298 effect in ARO cells. Previous studies in lovastatin have been emphasized on the inhibition of Ras farnesylation because overexpression or mutations of Ras were frequently observed in tumors (38, 39). However, recent studies have indicated that inhibition of geranylgeranylation, but not farnesylation, is the main mechanism regulating the lovastatin-induced apoptosis. Both geranylgeranylation and farnesylation have been suggested to play an important role in regulating cancer cell survival (30, 40). Consistent with these reports, our results also showed that both geranylgeranylation and farnesylation are required in ARO cell survival, and the prevention of lovastatin-induced apoptosis by GGOH further indicated that protein geranylgeranylation, but not farnesylation, played a crucial role in cellular survival when the lovastatin is present.
Exoenzyme C3 transferase, which is specific for Rho proteins (RhoA, RhoB, and RhoC), but not the other Rho family members (such as Rac1 and Cdc42), has been used to evaluate the functions of Rho proteins through ADP-ribosylation to inactivate the Rho proteins. Our study also showed that treatment of ARO cells with C3 exoenzyme resulted in apoptosis within 48 h. The Rho pathway has been suggested to be involved in the regulation of ARO cell survival. The activities of RhoA and Rac1, but not Ras, were suppressed in lovastatin-induced apoptosis of ARO cells (Fig. 5), suggesting that activation of the Rho family prevents the lovastatin-induced apoptosis in ARO cells.
RhoA kinase, a direct intermediate effector of RhoA, has been implicated in the regulation of RhoA signaling. In the present study, RhoA kinase inhibitor, Y-27632, was used to evaluate the role of RhoA/RhoA kinase signal pathway in the prevention of apoptosis. Treatment of ARO cells with Y-27632 induced apoptosis and decreased cell viability. These findings suggested that RhoA/RhoA kinase pathway is involved in the regulation of survival signaling of ARO cells. However, we cannot rule out that other geranylgeranylated proteins (such as Rac1) may also play important roles in preventing lovastatin-induced apoptosis, since the lovastatin-induced suppression of Rac1 activation was also restored by cotreatment of ARO cells with GGOH or mevalonate. In addition, CHX enhanced the apoptotic effect of TNF or the agonistic Fas antibody in ARO cells. In contrast, CHX prevented the lovastatin-mediated apoptosis in ARO cells, suggesting that there are labile proapoptotic factors involved in lovastatin-mediated death pathway in ARO cells.
Pan et al. (41) combined manumycin A and paclitaxel to treat the anaplastic thyroid cancer cells and showed that the enhanced apoptotic effect caused by combined treatment with paclitaxel and manumycin A was due to the release of cytochrome c from mitochondria to cytoplasm and the activations of caspases-3, -8, and -9. In addition, Di Matola et al. (42) and Vitale et al. (43) also reported that lovastatin could induce apoptosis in papillary thyroid cancer cells through inhibition of the protein prenylation. This apoptotic process is CHX sensitive, p53 independent, and involved in activations of caspase-3 and caspase-6 via cytochrome c releasing from mitochondria. In consistent with their findings, we demonstrated that lovastatin-induced apoptosis involved cytochrome c release, caspase-9 activation, and proteolytic cleavage of PARP following the activation of caspase-2 and -3 but not caspase-8 activation.
Although our present study demonstrated that lovastatin induced the occurrence of apoptosis in the ARO cells in vitro, the effective apoptosis-inducing concentrations of lovastatin related to tissue concentrations achieved when this drug is used in humans still needs further investigation. Statin (HMG-CoA reductase inhibitors) treatment induced a suppression of tumor growth and the occurrence of apoptosis in vitro and in vivo. The concentrations of statins used in cell culture models are relatively high and are not easily reached in vivo. The dose of lovastatin used for lowing serum cholesterol in animal models is about 1.5–2.5 mg/kg weight, but 0.25–1.0 mg/kg body weight is used in human clinical treatment (44). In a phase I study, on the other hand, the plasma concentrations of lovastatin measured in cancer patients are also relatively low (0.1–3.9 µM) (45). Because the myopathy and hepatotoxicity caused by the statin treatment is seldom observed in clinical long-term therapy, the use of lovastatin (even at a dose as high as 80 mg/d) for clinical therapeutic purpose in hypercholesterolemia is quite safe (46, 47). Previous reports, however, indicated that treatment of the patients with statins at the doses used for coronary artery disease prevention could cause a significant reduction of colon cancer incidence (48). Moreover, lovastatin treatment induced cellular differentiation in ARO cells (at a dose of 10 µM or less for cell culture experiment) and in anaplastic thyroid cancer cells (at a dose of 80 mg/d for patients in a clinical trial) (32). Accordingly, statins at lower concentrations than those used in the present study may possibly be effective. We believe that the effective doses of statins could be reduced by combined treatment of cancer cells with statins and the well-established chemotherapeutic drugs. However, the dose of statins used for cancer therapy needs to be further studied, and the derivatives of statins need to be intensively developed. Moreover, lovastatin could induce the differentiation in the thyroid cancer cells and thereafter made them more sensitive to radioactive iodine therapy, suggesting the clinical potential applications of lovastatin in thyroid cancer treatment.
In conclusion, both protein geranylgeranylation and farnesylation are required for ARO cell survival, and lovastatin-induced occurrence of apoptosis is through inhibiting protein geranylgeranylation of the Rho family but not farnesylation of the Ras family. In contrast to TNF and Fas signaling mechanisms, lovastatin-induced apoptosis required de novo protein synthesis.
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Footnotes |
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Abbreviations: AMC, 7-Amino-4-methylcoumarin; ATC, anaplastic thyroid cancer; CHX, cycloheximide; DTT, dithiothreitol; FOH, farnesol; FPP, farnesyl pyrophosphate; FTase, farnesyl transferase; GGOH, geranylgeraniol; GGPP, geranylgeranyl pyrophosphate; GGTase, geranylgeranyl transferase; HMG-CoA, 3-OH-3-methyl-glutaryl CoA; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; PARP, poly (ADP-ribose) polymerase; PMSF, phenylmethylsulfonylfluoride.
Received January 23, 2003.
Accepted for publication May 16, 2003.
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