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Original Studies |
Inhibit Growth and Induce Apoptosis of Human Papillary Thyroid Carcinoma Cells
Third Department of Internal Medicine (K.O., T.E., K.H., T.O.), Yamanashi Medical University, Yamanashi 409-3898, Japan; and Endocrine Research Laboratory (J.M.H.), West Los Angeles Veterans Affairs Medical Center and University of California School of Medicine, Los Angeles, California 90073
Address all correspondence and requests for reprints to: Toshimasa Onaya, M.D., Third Department of Internal Medicine, Yamanashi Medical University, 1110 Shimo-Kato Tamaho, Yamanashi, 409-3898 Japan. E-mail: onayat{at}res.yamanashi-med.ac.jp
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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(PPAR)
induce apoptosis and exert antiproliferative effects on several
carcinoma cell lines. The present study investigates the expression of
PPAR and the possibility that agonists for PPAR also inhibit the
growth of human thyroid carcinoma cells. We examined this hypothesis
using six cell lines, designated BHP thyroid carcinoma cells, which
originated from patients with papillary thyroid carcinoma. RT-PCR
analysis revealed that the thyroid carcinoma cell lines BHP2–7, 7–13,
10–3, and 18–21 express PPAR. More PPAR was expressed in
carcinoma than in adjacent normal thyroid tissue in three of six
samples of human papillary carcinoma of the thyroid.
PPAR-positive thyroid carcinoma cells were treated with agonists of
PPAR, troglitazone, BRL 49653, and
15-deoxy-
12,14-prostaglandin J2. Troglitazone (10
µmol/L), BRL 49653 (10 µmol/L), and
15-deoxy-12,14-prostaglandin J2 (1 µg/mL) decreased
[3H]thymidine incorporation and reduced cell number,
respectively, in BHP carcinoma cell lines that expressed PPAR. Under
low serum conditions, ligands for PPAR induced condensation of the
nucleus and fragmentation of chromatin into nucleosome ladders. These
findings indicate that the death of thyroid carcinoma cells is a form
of apoptosis.
To investigate the molecular mechanism of the apoptosis, we assessed expression of the apoptosis-regulatory genes bcl-2, bax, and c-myc. Troglitazone significantly increased the expression of c-myc messenger RNA but had no effect on the expression of bcl-2 and bax in thyroid carcinoma cells. These results suggest that, at least in part, the induction of apoptosis in human papillary thyroid carcinoma cells may be due to an increase of c-myc.
Troglitazone (500 mg/kg·day) significantly inhibited tumor growth and prevented distant metastasis of BHP18–21 tumors in nude mice in vivo.
Taken together, these results suggest that PPAR agonist inhibit cell
growth of some types of human thyroid cancer.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The peroxisome proliferator-activated receptor (PPAR) belongs to
the nuclear hormone receptor superfamily, and it plays an important
role in the differentiation of adipocytes (8, 9). Ligands
for PPAR induces apoptosis and exert antiproliferative effects on
several carcinoma cell lines (10, 11, 12, 13). In the present
study, we examined the expression of PPAR and the effects of PPAR
ligands on the growth of human papillary thyroid carcinoma cells. We
also investigated the ability of PPAR agonist to inhibit the growth
of thyroid carcinoma in vivo.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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All thyroid papillary carcinoma cell lines (BHP2–7, 7–13, 10–3, 14–9, 18–21, and 19–24) were maintained in RPMI 1640 medium supplemented with 10% FBS in a 5% CO2-95% air atmosphere at 37 C, as described previously (14, 15). Neoplastic human thyroid tissues [papillary carcinoma (n = 6), follicular adenoma (n = 2)] and adjacent normal thyroid tissue (n = 4) were surgically resected with the informed consent of the patients.
Chemicals
Troglitazone was provided by Sankyo Co., Ltd. (Tokyo, Japan). Pioglitazone was provided by Takeda Pharmaceutical Co. (Osaka, Japan). All other reagents were purchased from Sigma (St. Louis, MO).
RT-PCR
Total RNAs were prepared using acid-guanidium thiocyanate phenol
chloroform (16). RNA (10 µg) was reverse transcribed
with Rous-associated virus reverse transcriptase (Takara Shuzo Co.,
Kyoto, Japan) at 42 C for 60 min in a 40-µL mixture in the presence
of random primer. One microliter of a reverse-transcribed mixture was
amplified by PCR. The primers for PPAR were
5'-TCTGGCCCACCAACTTTGGG-3' (nucleotides 113–132, upstream) and
5'-CTTCACAAGCATGAACTCCA-3' (nucleotides 453–472, downstream)
(17). RT-PCR efficiency was confirmed in all samples by
amplifying human glyceraldehyde-3-phosphate dehydrogenase (GAPDH) using
the primers (sense) 5'-AACGTGTCAGTGGTGGTGGACCT-3' (nucleotides
775–794) and (antisense) 5'-ATGGCCCACATGGCCTCCAA-3' (nucleotides
1042–1061) (18). The primers using for amplification of
PPAR and GAPDH were designed to span the 2nd intron and 8th intron,
respectively. PCR products were sequenced using a Cycle Sequencing Kit
(Takara Shuzo Co.).
[3H]Thymidine incorporation
Subconfluent cells in 24-well tissue culture plates were washed twice with phosphate-buffered saline (PBS) and incubated with the indicated concentrations of test substances in 1 mL RPMI 1640 medium supplemented with 0.1% or 10% FBS for 4 h. The cells were then incubated with 0.5 µCi [3H]thymidine per well for 4 h, washed twice with 1 mL ice-cold PBS, harvested with 1 mL PBS containing 100 mg trypsin and 1 mmol/L EDTA, and sonicated. The amount of trichloroacetic acid-precipitable (10%) radioactivity was measured by liquid scintillation counting. Thymidine radioactivity was normalized by DNA content.
Cell counting
Cells were seeded at a density of 1 x 104 cells per well in 24-well tissue culture plates in 1.0 mL RPMI 1640 medium supplemented with 10% FBS with or without the indicated factors. The medium was changed every other day. After 72 h in an atmosphere of 5% CO2-95% air at 37 C, cells were detached from plates by incubation with 500 µL PBS containing 100 mg trypsin and 1 mmol/L EDTA. Cells were counted using a hemocytometer.
Measurement of apoptosis
BHP18–21 thyroid carcinoma cells cultured on cover slips were incubated with or without 10 µmol/L troglitazone in RPMI 1640 medium supplemented with 0.1% FBS for 24 h. The cells were fixed with 1% glutaraldehyde and stained with 1 mmol/L bisBenzimide (Hoechst 33342; Sigma). Apoptotic bodies were observed by fluorescent microscopy.
DNA fragmentation was visualized by autoradiography. Confluent cells in culture dishes were incubated with indicated concentration of troglitazone in RPMI 1640 medium supplemented with 0.1% or 10% FBS, then harvested at various times. DNA was extracted, 3'-end labeled, and resolved by electrophoresis as described (19).
Northern blotting
Total RNA (20 µg) was denatured by incubation with 50%
formamide and resolved by electrophoresis through a 1% agarose gel
containing 6.0% formaldehyde and 20 mmol/L morpholinepropane sulfonic
acid buffer. RNA was then blotted onto nitrocellulose membranes. Equal
loading per lane was verified by ethdium bromide staining of 18S and
28S ribosomal RNA, which was visualized and photographed under
ultraviolet illumination. After prehybridization for 4 h at 42 C
in 50% deionized formamide containing 5x SSC, 50 mmol/L sodium
phosphate (pH 6.7), 40 mg/mL denatured salmon sperm DNA, and 4x
Denhardt’s solution (50x Denhardt’s solution, 10 g/L
polyvinylpyrrolidone, 10 g/L Ficoll, and 10 g/L BSA), the membranes
were hybridized with 32P-labeled complementary
DNA (cDNA) overnight at 42 C. cDNAs for human c-myc,
bax, and bcl-2 were labeled with
[
-32P]deoxy-cytidine triphosphate
using a random primer labeling kit (Takara Shuzo Co.). Blots were
washed in 2x SSC, 0.1% SDS three times at room temperature for 10
min, then in 0.1x SSC, 0.1% SDS three times at 50 C for 20 min.
Northern analysis was repeated three times. The membranes were exposed
to an imaging plate, and densitometric analysis of results was
performed using a Bas 2000 image analyzer (Fuji Photo Film Co., Ltd., Tokyo, Japan).
Murine studies in vivo
BHP18–21 thyroid carcinoma cells (5 x 106) in 0.1 mL PBS were injected sc into the trunk of 8 male BALB/c nude mice at 6 weeks of age. Treatment began on the day after injection and was continued for 8 weeks. Control mice (4 mice per group) received solvent (dimethylsulfoxide) only or troglitazone (500 mg/kg·day) orally by gavage. Tumors were measured every week, and size was calculated using the following formula: A (length) x B (width) x C (height) x 0.5236. After 8 weeks, nude mice were killed and distant metastasis was searched macroscopically. Tumor, liver, lung, and spleen were fixed and stained for histological analysis. All experiments were conducted in accordance with the NIH Guide for the Care and Use of Laboratory Animals. The experimental protocol was approved by the Animal Care and Use Committees of Yamanashi Medical University.
Statistical analysis
Samples were examined in triplicate wells. Data are presented as means ± SD. Statistical analysis was performed by one-way ANOVA. Statistical significance was set at P less than 0.05. Scheffé’s F post hoc method detected significant differences between group means.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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in thyroid carcinoma cells
We studied the expression of PPAR in six human papillary
thyroid carcinoma cells using RT-PCR and specific primers.
Amplification by RT-PCR yielded a DNA fragment of the predicted size
and revealed PPAR messenger RNA (mRNA) in four of six papillary
thyroid carcinoma cell lines, namely BHP2–7, BHP7–13, BHP10–3, and
BHP18–21 (Fig. 1
). In contrast, the
human papillary carcinoma cell lines BHP14–9 and BHP19–24 did not
express PPAR mRNA.
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mRNA in human thyroid tissues was also
investigated. We analyzed cDNAs prepared from 12 human thyroid tissues
(6 papillary carcinoma, 4 normal thyroid, and 2 adenomas) using RT-PCR.
Of the 6 papillary carcinoma tissues, 3 expressed PPAR mRNA. In
these samples, PPAR mRNA was not expressed in adjacent normal
thyroid tissues (Fig. 2). Furthermore,
PPAR mRNA was not expressed in any other normal or adenoma thyroid
tissue investigated.
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Troglitazone decreased
[3H]thymidine incorporation into all thyroid
carcinoma cell lines that expressed PPAR mRNA.
Troglitazone (10 µmol/L) in 10% FCS significantly
decreased [3H]thymidine incorporation into
BHP2–7, 7–13, 10–3, and 18–21 cell lines by 52, 47, 55, and 44%,
respectively (P < 0.05). In contrast,
[3H]thymidine incorporation into BHP14–9 and
BHP19–24 cells was not inhibited by 10 µmol/L
troglitazone in 10% FCS (Fig. 3). Under low serum conditions (0.1%
FCS), troglitazone (10 µmol/L) reduced
[3H]thymidine incorporation into BHP2–7,
7–13, 10–3, and 18–21 cells to a level below 1% of the control. In
the presence of troglitazone (10 µmol/L) in 0.1% FCS,
cells became deformed and detached within 24 h. Wy14,643 (10
µmol/L) and all-trans-retinoic acid (10 µmol/L) did not
reduce [3H]thymidine incorporation into
BHP2–7, 14–9, and 18–21 cells (data not shown).
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agonists on the growth of human thyroid
carcinoma cell lines
Troglitazone (10 µmol/L) and BRL 49653
(10 µmol/L) significantly decreased numbers of BHP2–7, 7–13, 10–3,
and 18–21 thyroid carcinoma cells compared with control values
(P < 0.05) (Table 1). In
contrast, these agents did not affect the number of BHP14–9 and 19–24
thyroid carcinoma cells that did not express PPAR.
15-deoxy-12,14-prostaglandin J2 (prostaglandin J2; 1 µg/mL)
significantly inhibited the growth of BHP7–13 and BHP18–21 cells, but
not BHP14–9 cells. Wy14,643 (10 µmol/L), a PPAR agonist, did not
influence the growth of any thyroid carcinoma cell lines examined.
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Figure 4, A and B, shows the
morphological changes induced by troglitazone. BHP18–21
cells in logarithmic growth phase were transferred into 0.1% FCS RPMI
1640 medium with or without 10 µmol/L troglitazone.
Cells incubated with troglitazone lost cell-to-cell
contact. Fluorescent staining revealed fragmentation and condensation
of the nucleus (Fig. 4, C and D).
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). In
contrast, 10 µmol/L troglitazone in 0.1% FCS did not
induce DNA fragmentation on BHP14–9 thyroid carcinoma cells that did
not express PPAR. Troglitazone in 0.1% FCS induced DNA
fragmentation on BHP18–21 cell in a dose-dependent manner. However,
under 10% FCS conditions, even 10 µmol/L troglitazone
did not apparently induce DNA fragmentation (Fig. 5B). To induce DNA
fragmentation on BHP18–21 cells under 10% FCS condition, more than
100 µmol/L troglitazone was required (data not
shown).
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To investigate the molecular mechanism of apoptosis, we evaluated
the expression levels of apoptosis-regulated genes in BHP18–21 cells
using c-myc, bcl-2, and bax cDNA as
probes. Troglitazone in 0.1% FCS significantly and
dose-dependently increased c-myc mRNA levels in BHP18–21
cells. Densitometric data showed 10 µmol/L troglitazone
in 0.1% FCS increased c-myc mRNA levels by 3.0-fold
compared with the control (Fig. 6A).
However, in 10% FCS 10 µmol/L troglitazone increased
c-myc mRNA level only by 1.3-fold of control. Figure 6B
shows the time course of c-myc mRNA expression.
Troglitazone (10 µmol/L) in 0.1% FCS increased levels
of c-myc mRNA within 2 h and continued to do so for
12 h. In contrast, expression levels of bcl-2 and
bax genes were not affected by 10 µmol/L
troglitazone.
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We evaluated the antitumor effect of troglitazone
in vivo using BHP18–21 thyroid carcinoma cells in BALB/c
nude mice. Histological analysis of BHP18–21 tumors from untreated
mice revealed undifferentiated thyroid carcinoma tissue and distant
metastasis of tumor in the liver (Fig. 7, A and B). Troglitazone visibly inhibited the growth of
BHP18–21 tumors (Fig. 7, C and D).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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mRNA. Interestingly, four PPAR-positive thyroid
carcinoma cells could form a tumor, if these cells were transplanted to
nude mice. In contrast, PPAR-negative cells could not form a tumor
in nude mice. These observations suggest that PPAR expression might
be related to tumor progression. We also demonstrated expression of
PPAR mRNA in three of six human papillary carcinoma tissues. It is
noteworthy that PPAR mRNA was undetectable in the adjacent normal
thyroid tissues. Additionally, PPAR mRNA was not expressed in any
thyroid adenoma tissues examined. These findings suggest that the
prominent expression of PPAR mRNA is a feature of thyroid carcinoma.
Elstner et al. (10) reported that breast cancer
cells express a higher level of PPAR protein than normal breast
epithelial cells. Our data agree with these findings. However, we could
not find any histological or clinical difference between
PPAR-positive and -negative thyroid papillary carcinoma. Further
study is required to understand the relationship between PPAR
expression and the growth and tumorigenecity of thyroid neoplasms.
Because PPAR was expressed in four thyroid carcinoma cell lines, we
examined the effects of PPAR agonists on these lines. The growth of
these four thyroid papillary carcinoma cells was inhibited by
troglitazone or BRL 49653, synthetic ligands
for PPAR, and prostaglandin J2, a natural ligand for PPAR. In
contrast, PPAR agonists did not inhibit the growth of
PPAR-negative thyroid carcinoma cells. Furthermore, Wy14,643 or
all-trans-retinoic acid, a PPAR agonist or retinoic acid
receptor agonist, did not affect the growth of any thyroid carcinoma
cells examined. These results suggest that the inhibition of thyroid
carcinoma cells is specifically mediated through PPAR.
Troglitazone inhibits growth by inducing apoptosis in several carcinoma cells (10, 11, 13). We examined the notion that apoptosis is induced during the inhibition of thyroid carcinoma cell growth. We demonstrated that DNA from BHP18–21 cells undergoing death induced by troglitazone in 0.1% FCS showed chromatin fragmentation into nucleosome ladders. Furthermore, morphological observation revealed that troglitazone caused nuclear condensation and fragmentation. These findings indicate that troglitazone induced apoptosis and decreased the number of thyroid carcinoma cells.
The mechanism by which PPAR agonists induce apoptosis remains
unknown. Many genes are involved in the progression of apoptosis. To
investigate the molecular mechanism underlying the apoptosis of thyroid
carcinoma cells, we evaluated apoptosis-related gene expression. We
found that troglitazone dose-dependently increased
c-myc proto-oncogene mRNA. Furthermore, serum deprivation
potentiated the effect of troglitazone on the induction of
c-myc mRNA and apoptosis. In marked contrast, the expression
levels of bcl-2 or bax, which are survival and
apoptotic genes, respectively (20, 21), were not affected
by troglitazone. The results of dose-response studies lead
us to conclude that apoptosis by troglitazone may be, at
least in part, due to increase of c-myc. The inappropriate
expression of c-Myc induces or sensitizes cells to apoptosis
(22). Evan et al. (23) reported
that the overexpression of c-myc rendered fibrobrasts prone
to cell death on serum deprivation and led to the induction of
apoptosis by various means. Our findings are in agreement with these
observations. However, further study is required to reveal the role of
c-myc in apoptosis.
In 10% FCS condition, 10 µmol/L troglitazone reduced
[3H]thymidine incorporation and cell number of
PPAR-positive thyroid carcinoma cells. However, DNA fragmentation
was not clearly observed. One of the possibilities of these
inconsistencies might be due to the sensitivity of DNA fragmentation
assay. Another possibility is that troglitazone might
inhibit the growth of thyroid carcinoma cells by other mechanism than
apoptosis. To clarify this subject, we are trying to identify the gene,
which is responsible for the growth inhibition by
troglitazone in 10% FCS using differential display
technique.
Our animal studies revealed that troglitazone also
inhibits the growth of thyroid carcinoma cells in vivo. Mice
inoculated with tumor cells and given only solvent developed sc tumors
with distant metastasis in the liver. In contrast, mice treated with
troglitazone did not develop tumors and distant
metastasis. The doses of troglitazone applied in the
present study (500 mg/kg·day) is higher than human dose and dose
titration experiment must be required. However, it is noteworthy that
troglitazone inhibits tumor growth without affecting the
mean blood chemistries and hematopoietic values (11).
Pioglitazone, another synthetic thiazolidinedione, also
exerts growth inhibitory effect on BHP18–21 cells (data not shown).
Troglitazone is no longer widely used, but
Pioglitazone is used to treat patients with type 2
diabetes mellitus. Although further study using different animal models
is required to clarify antitumor effects, thiazolidinedione compounds
might be useful as therapeutic agents in treating thyroid carcinoma
that expresses PPAR.
The present study examined four thyroid carcinoma cell lines
that expressed PPAR mRNA. These PPAR-positive thyroid carcinoma
cell lines express Pax8 and/or TTF1, but not thyroid-specific proteins
such as thyroglobulin, thyroid peroxidase, TSH receptor, and Na/I
symporter (14, 15). Therefore, these cell lines might be
considered models of dedifferentiated papillary carcinoma. PPAR
agonists exerted antiproliferative effects on these dedifferentiated
cells. Thus, PPAR agonists might have therapeutic benefit even in
the treatment of undifferentiated thyroid carcinoma that does not
express thyroid-specific proteins.
In summary, we showed that PPAR is expressed by four thyroid
carcinoma cell lines and several thyroid carcinoma tissues. We
demonstrated that PPAR agonists inhibit growth and induce apoptosis
in these cell lines and that troglitazone inhibits the
growth of thyroid carcinoma cells in vivo. These findings
suggest that PPAR agonists may be useful agents with which to treat
thyroid cancer.
Received December 27, 2000.
Revised October 25, 2000.
Revised January 23, 2001.
Accepted February 5, 2001.
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References |
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C. A. French, E. K. Alexander, E. S. Cibas, V. Nose, J. Laguette, W. Faquin, J. Garber, F. Moore Jr, J. A. Fletcher, P. R. Larsen, et al. Genetic and Biological Subgroups of Low-Stage Follicular Thyroid Cancer Am. J. Pathol., April 1, 2003; 162(4): 1053 - 1060. [Abstract] [Full Text] [PDF]
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M. L. Martelli, R. Iuliano, I. Le Pera, I. Sama', C. Monaco, S. Cammarota, T. Kroll, L. Chiariotti, M. Santoro, and A. Fusco Inhibitory Effects of Peroxisome Proliferator-Activated Receptor {gamma} on Thyroid Carcinoma Cell Growth J. Clin. Endocrinol. Metab., October 1, 2002; 87(10): 4728 - 4735. [Abstract] [Full Text] [PDF]
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