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Endocrinological Oncology |
Endocrine Research Laboratory, 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: Jerome M. Hershman, M.D., Endocrinology Division 111D, West Los Angeles Veterans Administration Medical Center, Los Angeles, California 90073. E-mail: jhershmn{at}ucla.edu
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Abstract |
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Introduction |
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There are reports showing that cAMP may act as a growth inhibitor, but not stimulator, in some human thyroid carcinoma cell lines (4, 5, 6, 7). In these reports, the administration of a cAMP analog inhibited the growth of carcinoma cells, although TSH did not affect cAMP production. These results suggest that the role of the adenylate cyclase system in thyroid carcinoma cells might be different from that of normal thyroid cells, and that adenylate cyclase is activated by a substance other than TSH.
Recently, Endo et al. (10) established a malignantly transformed rat thyroid cell line and showed that a ß-adrenergic agonist inhibited the growth of this cell. Additionally, Lin et al. (11) reported overexpression of the ß2-adrenergic receptor messenger ribonucleic acid (mRNA) in human thyroid carcinoma tissues obtained at surgery. These results suggest the possibility that the activation of adenylate cyclase through the ß-adrenergic receptor regulates the growth of human thyroid carcinoma cells.
To further investigate this subject, we have established four new human thyroid carcinoma cell lines. In this paper, we report that some human thyroid carcinoma cell lines express the ß-adrenergic receptor and that cAMP induced through the stimulation of ß-adrenergic receptor inhibited the growth of these cell lines.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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[
-32P]Deoxy-CTP (3000 Ci/nmol),
[3H]CGP-12177 (45.0 Ci/mmol), and
[3H]thymidine (5 Ci/nmol) were purchased from Amersham
(Arlington Heights, IL). Nitrocellulose paper was purchased from
Schleicher and Schuell (Keene, NH), and x-ray film was obtained from
Eastman Kodak (Rochester, NY). All other reagents were purchased from
Sigma Chemical Co.(St. Louis, MO) unless otherwise indicated.
Cell culture
The human papillary thyroid carcinoma cell line, designated NP, was kindly provided by Dr. G. Juillard (Immunotherapy Laboratory, Univeristy of California-Los Angeles Department of Radiation Oncology). The BHP 17–10 cell line has been established in our laboratory (12). All cell lines used in these experiments were maintained in RPMI 1640 medium supplemented with 10% FBS in a 5% CO2-95% air atmosphere at 37 C, as previously described (12).
Establishment of new human thyroid carcinoma cell lines
Human papillary thyroid carcinoma tissues were obtained from four women (age range, 22–30 yr) at surgery. The method used to establish the cell lines was described previously (12). Briefly, these tissues were minced and digested with collagenase (2 mg/mL) and trypsin (50 mg/mL) in RPMI 1640 medium at room temperature for 60–90 min. Cells were cultured in RPMI 1640 medium supplemented with 10% FBS in flasks for 3–7 days. To establish cloned cell lines, cells were reseeded in 96-well plates after limiting dilution and cultured.
Northern gel analysis
Total RNA was prepared by the acid-guanidinium thiocyanate phenol chloroform method (13). Twenty micrograms of total RNA were denatured and electrophoresed in a 1% agarose gel containing 6.0% formaldehyde and 20 mmol/L morpholinepropane sulfonic acid (MOPS) buffer. RNA was then blotted onto nitrocellulose membrane with 20 x SSC (standard saline citrate). After prehybridization for 4 h at 42 C in a solution containing 50% deionized formamide, 5 x SSC, 50 mmol/L sodium phosphate (pH 6.7), 40 mg/mL denatured salmon sperm DNA, and 4 x Denhardt’s solution (50 x Denhardt’s is 10 g/L polyvinylpyrrolidone, 10 g/L Ficoll, and 10 g/L BSA), the membranes were hybridized to 32P-labeled complementary DNA (cDNA) overnight at 42 C. Blots were washed in 2 x SSC-0.1% SDS three times at room temperature for 10 min and then in 0.1 x SSC-0.1% SDS three times at 50 C for 20 min. Filters were exposed to Kodak XAR-5 film at -70 C using a fluorescent intensifying screen.
The cDNAs used in these studies were as follows: TTF-1 cDNA ligated
into pBluescript was provided by Dr. James Fagin (University of
Cincinnati, Cincinnati, OH). We used the
HindIII-ApaI fragment, which contains 1–331 bp
of TTF-1 cDNA (14). Pax-8 cDNA ligated into pGEM-T was provided by Dr.
Hisao Seo (Nagoya University, Nagoya, Japan). We used the
XhoI-PstI fragment, which contains 855-1156 bp
Pax-8 cDNA (15). The human thyrogloblin (Tg) cDNA was provided by
American Type Culture Collection (ATCC 57736, Rockville, MD). The human
thyroid peroxidase and TSH-R cDNAs were provided by Dr. Basil Rapoport
(University of California-San Francisco) (16, 17). The sodium/iodide
symporter cDNA was provided by Dr. Nancy Carrasco (Albert Einstein
College of Medicine, New York, NY) (18). The probes were labeled with
[-32P]deoxy-CTP using a multiple DNA-labeling system
(Amersham International, Aylesbury, UK) to a specific activity of
approximately 5–10 x 108 cpm/µg DNA.
Cell number measurement
Cells were seeded at a density of 5 x 103 cells/well of 48-well tissue culture plates in 0.5 mL RPMI 1640 medium supplemented with 10% FBS with and without the indicated materials. The culture medium was changed every 3 days. After culture for 6 days, the cells were detached from the plate by incubation with 500 µL PBS containing 1 mg/mL trypsin and 1 mmol/L ethylenediamine tetraacetate. Cell number was determined by counting in a hemocytometer.
[3H]thymidine incorporation
The cells grown to confluence in 24-well tissue culture plates were treated with the indicated concentrations of test substances in 1 mL of RPMI-1640 medium supplemented with 10% FBS for 24 h. Subsequently, cells were incubated with 0.5 µCi [3H]thymidine in each well for 4 h. Cells were then washed with 1 mL ice-cold PBS twice and harvested with 1 mL PBS containing 1 mg/mL trypsin and 1 mmol/L ethylenediamine tetraacetate and sonicated. Trichloroacetic acid (10%)-precipitable radioactivity was determined by liquid scintillation counting.
Assay of cAMP formation
The assay of cAMP response was performed as previously reported (19). In brief, the cells grown to 90% confluence in 24-well plates were washed with Hanks’ Balanced Salt Solution (HBSS) with 20 mmol/L HEPES (pH 7.4) twice. The cells were then incubated with the indicated substances in 300 µL HBSS with 20 mmol/L HEPES (pH 7.4) containing 1% (wt/vol) BSA and 0.5 mmol/L 1-methyl-3-isobutylxanthine at 37 C for 1 h. After incubation, the assay media were collected for cAMP measurement using a commercially available RIA kit (Incstar Co., Stillwater, MN).
Binding of [3H]CGP-12177 to BHP cells
[3H]CGP-12177 is a hydrophilic ß-adrenergic receptor radioligand. The [3H]CGP-12177 binding studies were carried out as previously described (20). Briefly, cells were grown to confluence in 24-well plates (2.5–4 x 105 cells/well). [3H]CGP-12177 (0.78–12.5 x 10-10 mol/L) was added in saturation binding experiments. All reagents were added in HBSS with 20 mmol/L HEPES (pH 7.4) containing 0.1% BSA. After 2-h incubation at 20 C, the cells were washed three times with the same buffer and solubilized with 1 mol/L sodium hydroxide. After neutralization by 1 mol/L hydrochloric acid, the solubilized material was counted in a scintillation counter. Nonspecific binding was defined as binding observed in the presence of 1 µmol/L propranolol.
Statistical analysis
Experiments were performed in triplicate wells, and all data are presented as the mean ± SD. All results are representative of at least two independent experiments. Statistical analysis was performed by one-way ANOVA. Statistical significance was set at P < 0.05. Scheffe’s F post-hoc method was used for detecting significant differences between group means.
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Results |
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All of the new BHP cells contained Pax-8 mRNA, approximately 3.1
kilobase (kb; Fig. 1A
). Additionally, only BHP 18–21
cells expressed TTF-1 mRNA (
2.4 kilobase; Fig. 1B). However, mRNAs
of thyroglobulin, TSH receptor, thyroid peroxidase, and sodium/iodide
symporter were not detected in these thyroid carcinoma cell lines by
Northern blot analysis (data not shown).
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8-Bromo-cAMP decreased [3H]thymidine
incorporation into all cell lines examined (Fig. 2). The
addition of 10 µmol/L 8-bromo-cAMP caused a significant decrease in
[3H]thymidine incorporation into BHP 2–7, 7–13, 17–10,
and 18–21 cell lines (P < 0.05). In contrast,
[3H]thymidine incorporation into NP cells was not
significantly inhibited even by 100 µmol/L 8-bromo-cAMP. 8-Bromo-cAMP
(1 mmol/L) reduced [3H]thymidine incorporation into BHP
2–7, 7–13, 10–3, and 18–21 cells to less than 1% of the control
value, although it reduced [3H]thymidine incorporation of
NP and BHP 17–10 cells by only 43% and 44%, respectively. The
addition of 100 µmol/L 8-bromo-cAMP significantly increased
[3H]thymidine incorporation by FRTL-5 rat thyroid cells
(data not shown).
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). The addition of 0.1 µmol/L forskolin
significantly decreased [3H]thymidine incorporation into
BHP 2–7, 7–13, 10–3, and 18–21 cell lines. At a concentration of 1
µmol/L, forskolin blocked [3H]thymidine incorporation
of BHP 2–7, 7–13, 10–3, and 18–21 cells to less than 5% of the
control value. NP and BHP 17–10 cells were more resistant to forskolin
with respect to [3H]thymidine incorporation. Even at a
concentration of 10 µmol/L, forskolin reduced
[3H]thymidine incorporation into NP and BHP 17–10 cells
by only 25% and 64%, respectively.
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).
In NP and BHP 17–10 cells, isoproterenol, epinephrine, and
norepinephrine did not affect [3H]thymidine incorporation
even at a concentration of 10 µmol/L.
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Forskolin (0.1 µmol/L), epinephrine (1 µmol/L), and
isoproterenol (0.1 µmol/L) significantly decreased the numbers of BHP
2–7, 7–13, 10–3, and 18–21 cells compared with the control values
(Table 1). In contrast, these treatments did not
significantly change the growth of NP and BHP 17–10 cells. TSH (1
mU/mL) did not influence the growth of all cell lines examined.
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TSH (1 mU/mL) did not stimulate cAMP production by any of the cell
lines examined (Table 2). Conversely, forskolin (1
µmol/L) remarkably increased the production of cAMP by 3.3- to
6.7-fold of the control value in every cell line examined. Furthermore,
the addition of 1 ng/mL cholera toxin induced the accumulation of cAMP
in all thyroid carcinoma cells. We found that isoproterenol (0.1
µmol/L) and epinephrine (1 µmol/L) stimulated cAMP production only
in the BHP 2–7, 7–13, 10–3, and 18–21 cell lines, by at least
5-fold over the control value. In contrast, isoproterenol (0.1
µmol/L) and epinephrine (1 µmol/L) did not significantly stimulate
cAMP production by NP and BHP 17–10 cells. The addition of 1 mmol/L
isoproterenol significantly increased cAMP production by NP cells,
although its stimulative effect was less than that on the BHP 2–7,
7–13, 10–3, and 18–21 cell lines.
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Figure 5 shows the binding of
[3H]CGP-12177 to BHP and NP cells. These saturation
binding studies revealed that BHP 2–7, 7–13, 10–3, and 18–21 cells
have ß-adrenergic receptors. Scatchard analysis of these binding
studies showed that the dissociation constants
(Kd) of BHP 2–7, 7–13, 10–3, and 18–21 cells
were 0.26, 0.19, 0.17, and 0.15 nmol/L, respectively, and the numbers
of receptor sites were approximately 7.8, 6.1, 5.3, and 6.8 x
103/cell, respectively. In NP cells, the
Kd was 0.25 nmol/L, and the number of receptors
was 1.5 x 103/cell. In contrast, saturable binding of
[3H]CGP-12177 was not observed in BHP 17–10 cells.
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Discussion |
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Controversial results have been reported on the effect of cAMP on thyroid carcinoma growth. Kimura et al. (5) showed that 8-bromo-cAMP reduces [3H]thymidine incorporation into NP and WRO thyroid carcinoma cells. In contrast, Hoelting et al. (8) reported that dibutryl cAMP did not affect the growth of FTC 133 human follicular thyroid carcinoma cells. This discrepancy might stem from the specific cell lines and cAMP analog used. In this study, we examined the effects of 8-bromo-cAMP on the growth of six human thyroid carcinoma cell lines, including four new cell lines. The present data demonstrate that the growth inhibitory effect of 8-bromo-cAMP is considerably higher on newly established BHP thyroid carcinoma cell lines than on NP and BHP 17–10 thyroid carcinoma cells. The different potency of 8-bromo-cAMP on the growth inhibition is probably attributable to the differences in cAMP-dependent protein kinase isozymes in these cell lines (25, 26, 27). It is noteworthy that all human thyroid carcinoma cell lines examined showed growth inhibition by 8-bromo-cAMP. In contrast, 8-bromo-cAMP significantly increased [3H]thymidine incorporation by FRTL rat thyroid cells. These results suggest the possibility that the inhibition of growth by cAMP might be a characteristic of some human thyroid carcinomas.
The mechanism by which cAMP inhibits the growth of these human thyroid carcinoma cells is still unknown. Cho-Chung et al. reported the growth inhibitory effect of cAMP analogs on a broad spectrum of human cancer cell lines, including breast, colon, lung, and gastric carcinoma (25, 26, 27). In these reports, they showed that the growth inhibition paralleled suppression of cellular protooncogene expression, such as c-myc and c-ras. The induction of protooncogene expression by cAMP needs to be compared in the new BHP and NP cells to further clarify the antiproliferative mechanism of cAMP on thyroid carcinoma cells.
In the second part of our study, we investigated a substance that
may promote cAMP production in these thyroid carcinoma cells. As a
first step, we examined the effect of TSH at various concentrations
(1–1000 mU/L), but we could not show any stimulatory effect of TSH on
all cell lines examined. In normal thyroid cells, binding of TSH to its
receptor leads to stimulation of the Gs protein
-subunit and subsequent activation of adenylate cyclase (28). We
showed that forskolin and cholera toxin significantly induced cAMP
production by all carcinoma cell lines tested. These results indicate
that the cause of impaired cAMP response to TSH is at the level of the
receptor and not at the level of Gs protein and
adenylate cyclase. Northern blot analysis showed the loss of expression
of TSH receptor mRNA. These results indicate that the TSH-adenylate
cyclase system is no longer important for the regulation of growth of
these human thyroid carcinoma cells.
In this study, we demonstrated that adrenergic receptor agonists stimulated cAMP production and mimicked the growth inhibitory effects of 8-bromo-cAMP on the new BHP thyroid carcinoma cells. The rank of potency of agonists was isoproterenol > epinephrine >> norepinephrine. These results suggest that the type of receptor expressed on the new BHP thyroid carcinoma cells is the ß2-type adrenergic receptor. Our finding is in agreement with a previous report of a malignantly transformed rat thyroid cell line (10).
This study also demonstrated that the new BHP thyroid carcinoma cell lines, which expressed a high number of ß-adrenergic receptors, are more sensitive to the growth inhibitory effects of cAMP. These results suggest the possibility that expression of ß-adrenergic receptor functions to inhibit the growth of these thyroid carcinoma cells.
The mechanism by which ß-adrenergic receptor expression is induced in these thyroid carcinomas cell lines is not known. Furthermore, the reason why the thyroid carcinoma cell lines, the growth of which is inhibited by a low concentration of cAMP, express more ß-adrenergic receptors also remains to be elucidated. For such studies, the new BHP thyroid carcinoma cells should be a useful model.
In summary, we successfully established four new human thyroid carcinoma cell lines from different patients. Using these cell lines, we demonstrated that cAMP acts as a growth inhibitor in these cells. Moreover, we showed that cAMP production was stimulated via the ß-adrenergic receptor, but not by the TSH receptor. Although the in vitro behavior of these thyroid carcinoma cell lines may not reflect that in vivo, it is noteworthy that the growth of some thyroid carcinoma cell lines was remarkably inhibited by ß-adrenergic agonist. These in vitro observations suggest that the growth inhibition by ß-adrenergic agonist may be characteristic of some human thyroid carcinomas.
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Footnotes |
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Received February 20, 1997.
Revised April 16, 1997.
Accepted April 22, 1997.
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References |
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2- and ß- adrenergic receptors and adenosine A1
receptor of FRTL-5 rat thyroid cells in relation to fucosyl GM1
ganglioside. Endocrinology. 124:2707–2710.[Abstract]
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