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Original Article |
on Thyroid Carcinoma Cell Growth
Dipartimento Medicina di Sperimentale e Clinica (M.L.M., R.I., I.L., I.S., L.C., A.F.), Facoltà di Medicina e Chirurgia di Catanzaro, Università di Catanzaro, 88100 Catanzaro, Italy; Dipartimento di Biologia e Patologia Cellulare e "Molecolare c/o Centro di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale delle Ricerche (C.M., S.C., M.S., A.F.), Facoltà di Medicina e Chirurgia di Napoli, Università degli Studi di Napoli Federico II", 80131 Naples, Italy; and 3Department of Pathology (T.K.), Brigham and Women’s Hospital, and Harvard Medical School, Boston, Massachusetts 02115
Address all correspondence and requests for reprints to: Alfredo Fusco, M.D., Dipartimento di Biologia e Patologia Cellulare e Molecolare, Facoltà di Medicina e Chirurgia di Napoli, Università degli Studi di Napoli, "Federico II", via Pansini 5, 80131 Naples, Italy. E-mail: afusco{at}napoli.com.
Abstract
Peroxisome proliferator-activated receptor 
(PPAR) is a nuclear receptor involved in such cellular processes as adipogenesis, inflammation, atherosclerosis, cell cycle control, apoptosis, and carcinogenesis. PPAR gene mutations have been found in 4 of 55 sporadic colon cancers, and a chimeric PAX8-PPAR1 gene frequently generates a chromosomal translocation in thyroid follicular carcinomas, implicating PPAR in tumor suppression. We investigated whether PPAR is involved in the growth regulation of normal and tumor thyroid cells. We found no mutations in PPAR exons 3 and 5 in human thyroid carcinoma cell lines and tissues. Moreover, 1 cell line (NPA) of 6 analyzed did not express PPAR. Treatment of NPA with PPAR agonists did not induce any inhibitory effect. Conversely, PPAR agonists and PPAR overexpression led to a drastic reduction of the cell growth rate in PPAR-expressing thyroid carcinoma cells. Restoration of PPAR expression in NPA cells induced cell growth inhibition; PPAR agonists induced further inhibition. Growth inhibition induced by PPAR agonists or by PPAR gene overexpression in thyroid carcinoma cells was associated with increased p27 protein levels and apoptotic cell death.
Should these data be confirmed, PPAR could be a novel target for innovative therapy of thyroid carcinoma, particularly anaplastic carcinomas, which represent one of the most aggressive tumors in mankind and are unresponsive to conventional therapy.
PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPAR) is a nuclear receptor that is involved in a wide range of cellular processes (1). It plays a central role in controlling the expression of numerous genes involved in adipocytes differentiation, lipid storage, and insulin sensitization (2, 3, 4). PPAR is activated by its natural ligands, e.g. prostaglandin J2 and fatty acid derivatives; but thiazolidinediones and nonsteroidal antiinflammatory drugs are synthetic ligands and agonists of this receptor (5, 6, 7, 8). However, PPAR has much wider functions, being involved in cell cycle control, inflammation, atherosclerosis, apoptosis, and carcinogenesis (1).
The human PPAR gene has nine exons, spans more than 100 kb, and is located on chromosome 3 at the 3p25 locus. Alternate transcription sites and alternate splicing determine three PPAR mRNA isoforms sharing exons 1–6 and differing in the 5' ends (9, 10). PPAR mRNA is abundantly expressed in adipose tissue, large intestine, and hematopoietic cells; is moderately expressed in kidney, liver, and small intestine; and is scarce in muscle cells (11).
In cancer, PPAR activation can bypass the requirement of retinoblastoma protein for withdrawal from the cell cycle (12). PPAR also inhibits the cell-growth-promoting E2F/DP transcription factors by increasing their phosphorylation status or by down-regulating PP2A protein phosphatase expression (13). Consistently, PPAR ligands decrease the growth rate of various malignant cell lineages and, in some cases, induce differentiation and apoptosis (14, 15, 16, 17, 18, 19). Four of 55 human colon carcinomas with monoallelic PPAR mutations have been recently found, indicating that human colon cancer is associated with loss-of-function mutations in PPAR (20). However, ligand activation in min mice, an animal model for familial adenomatous polyposis, seemed to cause increased polyposis (21). In addition, a t(2;3)(q13;p25) translocation involving PAX8 and PPAR-1 genes was identified in 5 of 8 thyroid follicular carcinomas (22). PAX8-PPAR-1 protein inhibited thiazolidinedione-induced transactivation by PPAR in a dominant negative manner.
More recently, a study on papillary thyroid carcinoma cells has shown that four out of six cell lines overexpress PPAR. These cell lines are inhibited in their growth in vitro and in vivo by troglitazone, which also induces apoptosis (22A ).
We investigated whether PPAR is involved in thyroid carcinogenesis, first by analyzing thyroid carcinomas tissues and cell lines for PPAR gene mutations, and then by examining the effects of PPAR stimulation on the growth regulation of thyroid carcinoma cell lines of different histotypes. The results of this study suggest that manipulation of PPAR may have applications in the treatment of thyroid tumors, particularly those refractory to conventional therapy.
Materials and Methods
Cell lines and tissue samples
The human thyroid carcinoma cell lines used in this study are described elsewhere (23). All cell lines were grown in DMEM containing 10% fetal calf serum. Tumor samples were obtained at the Laboratoire d’Histologie et de Cytologie (Centre Hospitalier, Lyon Sud, France), and they have been used with the approval of the French Institution.
DNA sequencing
PPAR cDNAs were PCR-amplified using the following primers, covering all the coding sequence: forward 5'-GTGTGAATTACAGCAAACCC-3', reverse 5'-ATCTCCACAGACACGACATT-3', forward 5'-AAGAGCCTTCCAACTCCCTC-3', reverse 5'-ACTCTGTGATCTCCTGCACA-3', forward 5'ATCCGCATCTTTCAGGGCTG-3', reverse 5'-AAGACTCATGTCTGTCTCCG-3'. The single-strand conformational polymorphism procedure, when performed, was as described previously (24). MWG Biotech (Münchenstein, Germany) sequenced the PCR products.
RT-PCR analysis
Total cellular RNA was extracted essentially as described elsewhere (27). cDNA was synthesized starting from 2 µg RNA using the reverse transcriptase enzyme (Promega Corp., Madison, WI) and according to standard protocols (27). The primers used to amplify PPAR cDNA were: 5'-TCTGGCCCACCAACTTTGGG-3' and 5'CTTCACAAGCATGAACTCCA-3'. As internal control, RT-PCR for ß-actin mRNA was also performed using the primers 5'-ATCTGGCACCACACCTTCTACAATGAGCTGCG-3' and 5'-CGTCATACTCCTGCTTGCTGATCCACATCTGC-3'. After denaturation of the samples at 95 C for 10 min, PCR was carried out for 40 cycles (95 C for 1 min, 55 C for 1 min, and 72 C for 1 min) followed by 72 C for 10 min. PCR products were electrophoresed in 1% agarose gels, stained with ethidium bromide, and checked for the expected length (PPAR, 360 bp; ß-actin, 838 bp). PAX8-PPAR mRNA was analyzed as described by Kroll et al. (22). In FB1 and NPA cells, the transfected exogenous PPAR cDNA was detected by PCR using the T7 forward primer and 5'CTTCACAAGCATGAACTCCA-3' reverse primer.
Colony assays
The pcDNA3 vector (Invitrogen, Carlsbad, CA), either empty or containing normal and nonfunctional, mutated full-length PPAR, was transfected in 60-mm dishes containing 2 x 105 cells, in duplicate, with the FuGene reagent (Invitrogen). Each dish was divided into two 100-mm dishes, and selection was started by the addition of G418 (Invitrogen) to the culture medium. Two weeks later, the selected cells were stained with crystal violet. The number of colonies and the average number of cells/colony were determined.
Protein extraction, Western blotting, and antibodies
Cells were scraped in ice-cold PBS and lysed in Nonidet-P40 lysis buffer [0.5% NP-40; 50 mM HEPES (pH 7); 250 mM NaCl; and 5 mM EDTA supplemented with NaF, Na3VO4, PMSF, aprotinin, and leupeptin]. Proteins were separated on polyacrylamide gel, transferred to nitrocellulose filter membranes (Hybond C; Amersham, Arlington Heights, IL), blocked in 5% nonfat dry milk, incubated with primary antibodies for 1 h at room temperature, and revealed by enhanced chemiluminescence (ECL, Amersham). All antibodies used for Western blot were from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA).
Growth rate analysis
A total of 5 x 104 cells were plated in 60-mm dishes. The next day, they were treated, or not, with 10 µM ciglitazone (Alexis Biochemicals, Lausen, Switzerland); and 24 or 48 h later, the cells were counted. In another set of experiments, the pcDNA3 vector, either empty or containing normal and mutated full-length PPAR cDNA under the transcriptional control of the CMV promoter, was transfected using the FuGene reagent (Invitrogen). The G418 selected clones were grown and used for RT-PCR, growth curve construction, and ciglitazone stimulation.
Apoptosis assays
The pcDNA3 vector, either empty or containing normal and mutated full-length PPAR cDNA, was transiently transfected with the FuGene reagent, in duplicate, in 60-mm dishes containing 1 x 104 of each cell type. After 72 h, an apoptosis-detection assay was performed using the Annexin V-EGFP Apoptosis detection Kit (CLONTECH Laboratories, Inc., Palo Alto, CA). The number of annexin or propidium iodide positive cells was evaluated for each dish.
An apoptosis assay was performed on ARO cells after 48 h treatment with 10 µM ciglitazone, using an Annexin V kit (MedSystems Diagnostics, Vienna, Austria), in parallel with the cell cycle analysis. The analysis of propidium iodide-negative and annexin V positive cells, considered early apoptotic cells, was performed by flow cytometry (FACScan; Becton Dickinson and Co., San Jose, CA).
Cell cycle analysis
Cell cycle profiles were performed on ARO cells treated, or not, with 10 µM ciglitazone for 48 h. Cells were analyzed using the Cycle Test Plus kit (Becton Dickinson and Co.), and the analysis was performed by flow cytometry (FACScan; Becton Dickinson and Co.).
Results
Expression of PPAR in thyroid carcinoma cells lines
To investigate whether the PPAR gene is involved in thyroid carcinogenesis, we analyzed PPAR gene expression in several human thyroid carcinoma cell lines: two cell lines from papillary carcinomas (NPA, NIM), one from a follicular carcinoma (WRO), and two from anaplastic carcinomas (ARO and FB-1). PPAR gene was expressed in normal thyroid tissue and thyroid carcinoma cell lines. However, PPAR expression was significantly higher in ARO than in the other cell lines; PPAR expression was not detected in the papillary carcinoma cell line, NPA (Fig. 1A
). Northern blot analysis confirmed this result (data not shown). We have analyzed the NPA cell line for possible genomic rearrangements by Southern blot analysis. No gross rearrangements have been found using different restriction enzymes (Fig. 1B) and probes (data not shown). Presumably, epigenetic modifications may account for the lack of expression of PPAR in this cell line.
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To determine whether the PPAR gene is altered in thyroid carcinogenesis, we examined the thyroid carcinoma cell lines listed above and 51 thyroid carcinomas (41 papillary, 5 follicular, and 5 anaplastic carcinomas) for somatic mutations in the cDNA, covering all the 9 PPAR exons. We used a combination of single-strand conformational polymorphism and direct sequence analysis for this study. No sample analyzed showed mutations (data not shown). We also looked for PAX8/PPAR-1 chimeric transcripts in the thyroid carcinoma cell lines and in the tumors, because a fusion between DNA-binding domains of thyroid transcription factor PAX8 to domains A–F of the PPAR-1, consequent to (2, 3)(q13; p25) translocation, has been reported for thyroid follicular carcinomas (22). No chimeric transcripts were detected in the thyroid carcinoma cell lines analyzed (data not shown).
Effect of ciglitazone stimulation on thyroid cells
Thiazolidinediones are high-affinity synthetic ligands and agonists of PPAR (8). Therefore, we treated four carcinoma cell lines (ARO, FB-1, FRO, and NPA) with ciglitazone to evaluate the effect of PPAR stimulation on cell growth. A preliminary dose-response experiment, in which 5 x 104 FB-1 cells were stimulated with 0, 1, 5, 10, or 50 µM ciglitazone and counted 24 h later, showed that growth inhibition was highest at 10 µM. Exponentially growing carcinoma cells were thus stimulated with 10 µM ciglitazone and counted after 24 or 48 h (Fig. 2). The growth of ARO, FB-1, and FRO cells, which express the PPAR gene, was inhibited by ciglitazone in a time-dependent manner, suggesting that PPAR activation interferes with cell cycle progression. Inhibition was highest in the very malignant ARO anaplastic carcinoma cell line. Conversely, NPA cells, which do not express the PPAR gene, did not respond to ciglitazone stimulation.
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The observation that ciglitazone-treated cells had a more pronounced fraction of G1 cells (22A ) prompted us to analyze the expression and activity of G1 cyclin-dependent kinases (CDK2, CDK4, and CDK6) and of their inhibitors (p21cip1, p27kip1, and p57kip2) in the treated cells, by Western blot. Levels of p27kip1 protein were significantly increased in the FB-1 and ARO cell lines, 24 and 48 h after treatment with ciglitazone (Fig. 3). Conversely, p27kip1 protein levels were unchanged in the ciglitazone-treated NPA cells (Fig. 3). These results correlate with PPAR mRNA expression and susceptibility of the four tested cell lines to growth rate inhibition by PPAR agonists. Hybridization of the Western blots with anti-p21cip1 antibodies showed that treatment did not alter p21cip1 expression (data not shown).
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inhibits thyroid carcinoma cell growth
To determine the effect of PPAR gene expression on thyroid carcinoma cell growth, we transfected exponentially growing ARO, FB-1, FRO, and NPA cells with a wild-type and a mutated nonfunctional PPAR construct or with the backbone pcDNA3 vector. Transfected cells were selected for 14 d and stained with crystal violet. The number of colonies was drastically reduced in the thyroid carcinoma cells transfected with the wild-type PPAR (wt PPAR) vs. those transfected with the backbone vector or with the mutated PPAR (mut PPAR) construct (Table 1 and Fig. 4). The number of the colonies was drastically reduced, even in ARO cells that express high levels of endogenous PPAR mRNA.
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overexpression on stable transfected clones
NPA and FB-1 cells, transfected with the wild-type and the mutated form of PPAR, were further characterized with RT-PCR and a forward primer from the vector and a reverse primer from the PPAR cDNA. Exogenous PPAR expression was found in the mRNA from both wild-type and mutated transfected NPA and FB-1 cells but not in untransfected cells or cells transfected with the empty vector (Fig. 5). Subsequently, we constructed a growth curve with several FB-1- and NPA-positive clones. Figure 6 shows that the growth rate of FB-1 and NPA clones was inhibited only when transfected with the wild-type full-length PPAR cDNA. We also analyzed the ability of wild-type PPAR-transfected NPA cell clones to respond to ciglitazone. Ciglitazone treatment inhibited the growth of NPA cell clones transfected with the wild-type PPAR but not the NPA cells transfected with the mutated PPAR or the backbone vector (Fig. 7).
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- and FB-1-transfected clones (Fig. 8 and data not shown). The expression of p21cip1 was unchanged in the transfected and untransfected NPA and FB-1 cell clones (data not shown).
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overexpression induces apoptosis
PPAR stimulation or overexpression increases apoptosis in several cell types (15, 16, 27, 28). Therefore, to verify whether PPAR expression exerts the same effect on thyroid carcinoma cell lines, ARO, FB-1, FRO, and NPA cells were transiently transfected with PPAR and analyzed with the Annexin V apoptotic assay. The percentage of propidium iodide-positive cells was significantly increased in all four thyroid carcinoma cell lines after transfection with the wild-type PPAR cDNA, compared with the same cells transfected with the empty vector or with the vector carrying mutated nonfunctional PPAR cDNA (see Table 2).
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To better investigate the mechanism of growth inhibition by PPAR activation, a flow cytometric cell cycle analysis was performed in parallel with a flow cytometric apoptosis assay on ARO cells treated, or not, with 10 µM ciglitazone. Representative cell cycle and apoptotic profiles are shown in Fig. 9. Ciglitazone seems to induce G0-G1 cell cycle arrest in this cell line, given that the percentage of cells in G0-G1 phase increases from 55% to 66%, the percentage of cells in S phase decreases from 38% to 30%, and the percentage of cells in G2-M phase decreases from 5.33% to 2.6%. At the same time, the percentage of apoptotic cells increases from 10.8% to 16.3%.
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A recent study showed that a chromosomal translocation involving the PPAR gene and leading to the generation of a chimeric PAX8-PPAR-1 gene is a frequent event in thyroid follicular carcinomas (22). Moreover, 4 somatic PPAR mutations have been identified among 55 sporadic colon cancers (20). In both cases, these mutations and rearrangements of the PPAR gene impair PPAR function; in particular, they affect thiazolidinedione-induced transactivation by PPAR in a dominant negative fashion, which suggests that PPAR exerts a tumor-suppressor function.
We have examined a panel of thyroid carcinoma tissues and cell lines of different histotypes for mutations in the PPAR cDNA, covering the coding sequence of the gene. We did not find any mutations. The human carcinoma cells examined did not contain any PAX8-PPAR-1 chimeric transcripts; consequently, impaired function to structural modifications of the protein could be excluded. Ciglitazone inhibited the growth of most of the thyroid carcinoma cell lines in a time-dependent manner, suggesting that activation of PPAR negatively regulates the cell cycle. The effect was more pronounced in the highly malignant ARO anaplastic carcinoma cell line consistent with abundant PPAR gene expression. Differently, the papillary carcinoma cell line NPA did not respond to ciglitazone. We found no evidence of sequence alterations in this line, and no gross genomic rearrangements have been found by Southern blot analysis. PPAR mRNA was absent from this cell line, which finding suggests a correlation between the capability of ciglitazone to inhibit growth and the functionality of the PPAR pathway. Moreover, besides inhibiting growth, transfection of wild-type PPAR cDNA in NPA cells restored the capability to respond to ciglitazone. The finding that the number of colonies was drastically reduced only in wild-type PPAR-transfected cells, and the reduced growth of stable cell clones, confirm that PPAR plays an important role in thyroid cell growth inhibition, as reported for other cell systems (14, 15, 16, 18, 19, 29, 34, 35, 36).
Although the mechanism whereby PPAR mediates growth inhibition in human thyroid carcinoma cells has yet to be elucidated, it may be connected to the cell cycle in other mammalian cells (22A ). We found that p27kip1 cell cycle inhibitor is important in PPAR-mediated cell growth arrest in thyroid cells. In fact, G1 cell cycle arrest was observed in FB1 and NPA cells transfected with PPAR and in ARO cells treated with ciglitazone. NPA cells, which do not express endogenous PPAR mRNA, are not growth-arrested by ciglitazone and do not show p27kip1 up-regulation. Ciglitazone-induced growth inhibition of FRO cells without an increase of p27kip1 may be attributable to apoptosis, because PPAR agonists induce apoptosis in thyroid cells (22A ). Alternatively, other p27-independent mechanisms of PPAR-mediated growth arrest could be involved in some cell lines, as hypothesized for other cell systems (37).
Because PPAR activation resulted in an apoptotic effect in choriocarcinoma cells (38), prostate cancer cells (18), endothelial cells (30), leukemic cells (30, 34, 36), and gastric cancer (27), we investigated whether PPAR overexpression might lead thyroid carcinoma cells to apoptotic death. PPAR over-expression induces G0-G1 cell cycle arrest in thyroid cells, as suggested by the p27kip1 expression analysis previously performed on several cell lines and by the FACScan analysis performed on ARO cells.
Even though further studies are required for a full comprehension of the mechanisms underlying growth inhibition and apoptosis induced by stimulation of the PPAR pathway, this study indicates that PPAR might be a novel target for innovative therapy of thyroid carcinoma, particularly the anaplastic histotype. In this direction, promising studies have been performed in patients with liposarcoma and prostate cancer. A clinical trial has been conducted with 3 patients with liposarcomas in whom troglitazone administration induced histological and biochemical differentiation in vivo (39), whereas 41 men with prostate cancer treated orally with troglitazone showed prolonged stabilization of prostate-specific antigen (40).
Acknowledgments
We thank the Associazione Partenopea per la Ricerche Oncologiche (APRO) for its support. We are grateful to Jean Gilder for editing the text.
Footnotes
This work was supported by grants from AIRC (Progetto Speciale Oncosoppressori), the Progetto Finalizzato "Biotecnologie" of the Consiglio Nazionale delle Ricerche, the MURST projects "Terapie antineoplastiche innovative" and "Piani di Potenziamento della Rete Scientifica e Tecnologica," and from the Ministero della Sanità.
Abbreviation: PPAR, Peroxisome proliferator-activated receptor .
Received December 27, 2001.
Accepted June 28, 2002.
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