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Original Studies |
Section of Endocrinology (M.C.Z., F.T., R.R., E.C.d.U.), Department of Biomedical Sciences and Advanced Therapies, University of Ferrara, 44100 Ferrara, Italy; and Biomeasure Incorporated (J.E.T., M.D.C.), Milford, Massachusetts 01757-3650
Address all correspondence and requests for reprints to: Ettore C. degli Uberti, M.D., Section of Endocrinology, Department of Biomedical Sciences and Advanced Therapies, University of Ferrara, Via Savonarola 9, 44100 Ferrara, Italy. E-mail: ti8{at}dns.unife.it
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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SRIF and various analogs have been shown to inhibit normal and neoplastic cell proliferation in vitro and in vivo (2) via specific SRIF receptors (SSTRs) (3) and possibly different postreceptor actions (4, 5). In addition, there is evidence that distinct SSTR subtypes are expressed in normal and neoplastic human tissues (6), conferring different tissue affinities for various SRIF analogs and variable clinical response to their therapeutic effects.
Medullary thyroid carcinoma (MTC) is a tumor originating from thyroid parafollicular C cells that produce calcitonin (CT) as well as several other peptides, including SRIF (7). Recently, Mato et al. (8) showed that SRIF and SSTRs are expressed in human MTC. It has been documented that SRIF and its analogs induce a decrease in plasma CT levels and a symptomatic improvement in MTC patients. However, the antiproliferative activity of SRIF analogs on tumor cells is still controversial (9, 10, 11) and the specific role of SSTR subtypes in cell growth regulation is currently under investigation. In this respect, development and assessment of SSTR subtype analogs selective on MTC cell growth may provide insight for clinical application.
In this study, we tested the effects of SSTR2 and SSTR5 agonists and of a SSTR2 antagonist on cell proliferation with a human MTC cell line, TT (12), characterized by the presence of a mutation involving exon 11 of the Ret proto-oncogene (13). Availability of these new SSTR subtype-selective agonists allowed us to gain insight into the individual functions of two SSTR subtypes, SSTR2 and SSTR5, in modulating the tumoral proliferation of parafollicular C cells. These observations may facilitate the rational development of novel drugs that more selectively interact with SSTR2 as a potential treatment for MTC.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The TT cell line was obtained from the American Type Culture Collection (Manassas, VA). This cell line, established
from a specimen obtained by needle biopsy from a 77-yr-old female with
MTC (12), consists of aneuploid transformed CT-producing
parafollicular cells that are characterized by the presence of a TGC to
TGG mutation (Cys to Trp) at exon 11 codon 634 in the Ret
proto-oncogene (13), a characteristic that we confirmed in
the cell line we worked with (data not shown). Moreover, TT cells
display an impaired expression of the tumor suppressor gene p53
(14). Immunohistochemistry studies demonstrated that TT
cells express CT and CT receptor (15), carcino-embrionic
antigen, SRIF, neurotensin, gastrin-releasing peptide, Leu- and
Met-enkephalin, paratormone-releasing peptide, chromogranin A, SP-I,
synaptophysin, neuron-specific enolase, 1,25-dihydroxyvitamin
D3 receptor, thyrosin hydroxylase,
-tubulin, and cytocheratin (16). TT cells secrete a
significant amount of CT and respond to changes in ionized calcium
levels (17). Therefore, this cell line seems suitable for
studies on parafollicular cell function and responses to endocrine and
pharmacological stimuli.
Cells were maintained in Ham’s Nutrient Mixture F12 with glutamine (EuroClone Ltd, Torquay, UK), supplemented with 10% FBS (Life Technologies, Inc., Milano, Italy), 100 U/mL penicillin, 0.1 mg/mL streptomycin, and 100 µg/mL amphotericin (EuroClone Ltd) at 37 C in a humidified atmosphere of 5% CO2 and 95% air.
Isolation of RNA and RT-PCR
Total RNA was extracted from subconfluent TT cells by using TRIzol (Life Technologies, Inc.), according to the manufacturer’s protocol. To prevent DNA contamination, RNA was treated with ribonuclease-free deoxyribonuclease (Promega Corp., Milano, Italy).
Using a first strand complementary DNA (cDNA) synthesis kit
(SuperScript Preamplification System for First Strand cDNA Synthesis;
Life Technologies, Inc.), 1 µg total RNA was reverse
transcribed with random hexamers according to the
manufacturer’s protocol. RT reaction was carried out in the Minicycler
(MJ Research, Inc., Watertown, MA) as described previously
(18). The cDNA (1 µL RT reaction) was then amplified by
PCR with 1 U Taq DNA polymerase (Life Technologies, Inc.) in the conditions recommended by suppliers. PCRs were
carried on using the oligonucleotide primers and the conditions listed
in Table 1
, describing the size of
expected fragments. PCR products were analyzed on a 2% agarose gel and
visualized by ethidium bromide staining. To assure that no
contamination occurred during the course of the RT-PCR procedure, two
kinds of negative control were prepared. The first negative control was
made by omitting the total RNA in the RT. The second was prepared by
replacing the cDNA mix with water in the PCR. The PCR was considered
useful only if no band was observed in the negative control lanes on a
2% agarose gel. Each PCR product was subjected to restriction enzyme
digestion and analyzed on 2% agarose gel to further confirm the
correct identification of the amplicons (data not shown).
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The SRIF analogs used in this study and their respective
affinities to the different SSTRs are listed in Table 2. Each compound, provided by Biomeasure
Inc. (Milford, MA), was resuspended in 0.01 N acetic acid
containing 0.1% BSA, to provide uniform solubility and prevent
nonspecific binding to the various preparation surfaces. Specificity
and selectivity of the analogs were determined by radioligand binding
assay on Chinese hamster ovary (CHO)-K1 cells stably transfected with
each of the SSTR subtypes, as described previously
(19).
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Biological activity of SSTR-selective agonists and
antagonists was evaluated by the calcium mobilization assay
(20) in CHO-K1 cells, expressing the human SSTR2 or SSTR5.
The cells were harvested by incubating in a 0.3% EDTA/PBS solution (25
C), and washed twice by centrifugation. The washed cells were
resuspended in HBSS for loading of the fluorescent
Ca2+ indicator fura-2AM. Cell suspensions
(approximately 100 cells/ml) were incubated with 2 mM
fura-2AM for 30 min at 25 C. Unloaded fura-2AM was removed by
centrifugation twice in HBSS, and the final suspensions were
transferred to a spectrofluorometer (Hitachi
F-2000, Salem, NH) equipped with a magnetic stirring mechanism and a
temperature-regulated cuvette holder. After equilibration to 37 C, the
SRIF analogs were added for measurement of intracellular
Ca2+ mobilization. The excitation and emission
wavelengths were 340 and 510 nm, respectively. In the SSTR2-expressing
cells (Fig. 1), BIM-23120 and BIM-23014
have been shown to stimulate intracellular Ca2+
mobilization (indicated as the ratio between stimulated and basal
value), whereas no effect has been observed with BIM-23627. In
addition, BIM-23197 and BIM-23190 were also highly potent in
stimulating Ca2+ mobilization (data not shown).
In the SSTR5-expressing cells (Fig. 2),
BIM-23206 and BIM-23014 have been shown to stimulate intracellular
Ca2+ mobilization, whereas BIM-23627 displayed
slight agonist activity in the range of 300-1000 nM. In the
SSTR2-expressing cells (Fig. 3),
BIM-23627 inhibited SRIF-induced intracellular
Ca2+ mobilization in a dose-dependent manner with
complete suppression of SRIF action at
10-7 M.
Therefore, the evaluation of intracellular Ca2+
mobilization demonstrated that the biological activity of the various
analogs was in keeping with their receptor binding profile.
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The effects of SSTR-selective agonists and antagonists on TT cell DNA synthesis were assessed by determining the rate of [3H]thymidine ([3H]thy) incorporation, as described previously (21). TT cells were plated in 24-multiwell plates (105 cells/well) and incubated for 48 h in a medium supplemented with 10% FBS in the presence of [3H]thy (1.5 µCi/mL; 87 Ci/mmol) with or without each SRIF analog at concentrations ranging from 10-6 to 10-9 M. Treatments were renewed after the first 24 h of incubation. After incubation, cell-associated radioactivity was counted in a scintillation spectrometer. Results (cpm per well) were obtained by determining the mean value of at least 6 experiments in quadruplicate. The viability of TT cells in control and treated cultures was evaluated by trypan blue staining after 24 and 48 h, and the number of viable cells was always 85–95%.
Cell proliferation
The effects of SSTR-selective agonists and antagonists on TT cell proliferation were assessed by the CellTiter 96 Aqueous NonRadioactive Cell Proliferation Assay (Promega Corp.), a colorimetric method for determining the number of viable cells in proliferation assays (22). Briefly, TT cells were plated in 96-multiwell plates (2 x 104 cells/well) and incubated for 48 h in a medium supplemented with 10% FBS in the presence or absence of each SRIF analog at concentrations ranging from 10-6 to 10-9 M. Treatments were renewed after the first 24 h of incubation. At the end of the incubation period, the plates were incubated for an additional 4 h at 37 C in a humidified 5% CO2 atmosphere with the staining solution. The absorbance at 490 nm was then recorded using an enzyme-linked immunosorbent assay plate reader (EASIA Reader; Medgenix, Camarillo, CA). Results (absorbance at 490 nm) were obtained by determining the mean value of at least 6 experiments in 8 replicates.
Statistical analysis
All values are expressed as the mean ± SE. A preliminary analysis was carried out to determine whether the data sets conformed to a normal distribution, and a computation of homogeneity of variance was performed using Bartlett’s test. The results were compared within each group and between groups using ANOVA. If the F values were significant (P < 0.05), Student’s paired or unpaired t test was used to evaluate individual differences between means.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To understand the individual role of SSTR2 and SSTR5 subtypes in
controlling parafollicular C cell proliferation, we evaluated whether
TT cells express SSTRs that could mediate a potential response to
selective compounds for individual SSTR subtypes. To address this
question, we isolated total RNA from cultured TT cells and performed
RT-PCR in the conditions described in Materials and Methods.
Integrity of cDNA was assured by the presence of the
glyceraldehyde-3-phosphate dehydrogenase (GAPDH) signal.
Positive amplification of SSTR1, 2, 3, 4, and 5 was found in the
examined cell line (Fig. 4),
demonstrating that these receptors are expressed in human MTC cell line
TT.
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Effect of selective SRIF analogs on TT cell [3H]thy incorporation
[3H]Thy incorporation values obtained with
10-9–10-6
M concentrations of SSTR2 preferential agonists (BIM-23120,
BIM-23197, BIM-23190, and BIM-23014), SSTR5 preferential agonist
(BIM-23206), and SSTR2 preferential antagonist (BIM-23627) are
presented in Fig. 5. As indicated,
BIM-23120 significantly suppressed [3H]thy
incorporation by 58–23% at concentrations ranging from
10-9 to
10-7 M.
BIM-23014 significantly suppressed [3H]thy
incorporation by 41–21% at concentrations ranging from
10-9 to
10-6 M.
[3H]Thy incorporation was slightly but
significantly reduced by BIM-23197 (-13%, P <
0.05) and BIM-23190 (-17%, P < 0.05) at
10-9
M. The SSTR5-selective agonist, BIM-23206,
significantly increased [3H]thy incorporation
in TT cells by 80–175%. The SSTR2-selective antagonist, BIM-23627,
did not alter TT cell [3H]thy incorporation
compared with untreated control cells.
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To examine in more detail the activity of SRIF analogs on TT cell
growth, their effect on viable cell number was also analyzed. The
effects of SSTR2 preferential agonists (BIM-23120, BIM-23197,
BIM-23190, and BIM-23014), SSTR5 preferential agonist (BIM-23206) and
SSTR2 preferential antagonist (BIM-23627) on viable TT cell number at
concentrations ranging from
10-9 to
10-6 M are
represented in Fig. 6. As indicated, all
SSTR2 preferential compounds significantly inhibited cell proliferation
when compared with untreated control cells at each concentration
tested. The selective SSTR5 agonist, BIM-23206, produced a slight
increase of TT cell proliferation (up to 11% at
10-8 M),
without reaching statistical difference from the untreated control
cells. The selective SSTR2 antagonist, BIM-23627, did not affect TT
cell growth, regardless of the concentration used.
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To further clarify whether SSTR2 is specifically involved in
mediating the antiproliferative activity of the two SSTR2 preferential
agonists, BIM-23120 and BIM-23014, [3H]thy
incorporation and cell growth were evaluated in TT cells exposed for
48 h to each compound either alone (at
10-7 M) or in
combination with BIM-23627, a selective SSTR2 antagonist, at equimolar
concentration (10-7
M). The inhibition of [3H]thy
incorporation induced by both BIM-23120 and BIM-23014 was totally
suppressed by cotreatment of TT cells with BIM-23627 (Fig. 7, top). TT cell proliferation
inhibition induced by BIM-23014 was significantly reduced from 46% to
10%, by cotreatment with BIM-23627. BIM-23627 totally blocked the
antiproliferative activity of BIM-23120 (Fig. 7, bottom).
Thus, the specific involvement of SSTR2 in mediating the inhibitory
effect of BIM-23120 and BIM-23014 on TT cell proliferation is further
substantiated.
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The finding that the highly selective SSTR5 agonist, BIM-23206,
significantly increased [3H]thy incorporation,
and slightly stimulated TT cell proliferation, whereas SSTR2
preferential compounds (BIM-23120 and BIM-23014) significantly
suppressed both [3H]thy incorporation and cell
proliferation prompted us to analyze the effects of BIM-23206 and
BIM-23120 (the most selective compound for SSTR2) in combination. In
this study, TT cell [3H]thy incorporation and
proliferation were examined, testing each agonist at
10-7 M in
combination with increasing doses (from
10-9 to
10-6 M) of the
other compound. The results are summarized in Fig. 8. Increasing concentrations of BIM-23206
(10-9–10-6
M) dose-dependently prevented the suppression of TT cell
[3H]thy incorporation (Fig. 8, top)
and proliferation (Fig. 8, bottom) produced by BIM-23120
(10-7
M). These data indicate an antagonism between
SSTR5 and SSTR2 preferential compounds. This may imply a complex
interplay between SSTR2 and SSTR5 in the control of cell proliferation
in the human TT cell line with negative and positive regulatory roles,
respectively.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In this study, RT-PCR analysis provided evidence that all five SSTR subtype messenger RNAs (mRNAs) are expressed in a human MTC cell line, TT, which displays all MTC cell characteristics (20, 23, 24). Recent studies have shown that the MTT cell line, a human-medullary carcinoma cell line variant derived from the TT cell line (14), expresses SSTR2, 3, 4, and 5 mRNAs, but not SSTR1 mRNA (25). The reason for the discrepancy between our findings and those of Medina et al. (25) is unclear. However, our detection of SSTR1 mRNA expression in TT cell line is an agreement with recent data of Mato et al. (8), showing that SSTR1, 2, 3, and 5 subtype mRNAs are detectable by RT-PCR in a series of human MTC, with predominant expression of SSTR2 and 5 subtypes. Normal human thyroid seems to predominantly express SSTR3 and 5, whereas follicular carcinoma cell lines display a different expression pattern, being SSTR1 and 3 the most represented (26).
There is increasing evidence that SRIF regulates cell proliferation either arresting cell growth via SSTR1, 2, 4, and 5 subtypes (27, 28, 29, 30) or inducing apoptosis via SSTR3 subtype (31). Until now, data concerning specific SSTR subtype involvement in MTC cell growth regulation have not been reported. In this study, we tested the ability of SRIF analogs with differing affinity and specificity for SSTR2 and 5 subtypes to influence TT cell growth, evaluating proliferative activity by means of number of viable cells and [3H]thy incorporation, which is considered an indirect measure of DNA synthetic activity.
All SSTR2 preferential agonists were able to significantly suppress TT cell number at concentrations ranging from 10-9 to 10-6 M, although some differences in the inhibitory effect on [3H]thy incorporation among these compounds were observed. BIM-23197 and BIM-23190 slightly but significantly (P < 0.05) reduced [3H]thy incorporation only at 10-9 M but not at 10-8 and 10-7 M, when their maximal inhibitory effect on cell number was apparent. However, all SSTR2 agonist compounds tested showed a trend for decreased efficacy with increasing concentration. Bell-shaped response curves are common for SRIF and, because BIM-23190 and BIM-23197 have severalfold greater affinity for SSTR2 than BIM-23014 and BIM-23120, the effect may have been more pronounced. The inhibition of [3H]thy incorporation and TT cell number by BIM-23120 and BIM-23014 at 10-7 M was not associated with any cytotoxic action, as demonstrated by trypan blue staining. Moreover, this effect was completely counteracted by cotreatment of TT cells with BIM-23627, a selective SSTR2 antagonist. Taken together, these results indicate that SRIF analogs BIM-23120 and BIM-23014 with preferential selectivity for SSTR2 inhibit TT cell proliferation specifically by interacting with SSTR2. Therefore, our findings support an inhibitory role for SSTR2 in regulating cell proliferation, as reported previously (4). Understanding the differential effects on both DNA synthesis and cell division of different SRIF analogs displaying relative selectivity for SSTR2 may be important in developing new compounds with specific antiproliferative activity.
Remarkably, we have shown that BIM-23206, a compound discovered to have a high affinity and specificity for SSTR5, unexpectedly induced TT cell [3H]thy incorporation but did not influence cell number, providing evidence that selective activation of SSTR5 in TT cell line promotes DNA synthesis with no effect on cell proliferation. These results prompted us to combine the selective SSTR5 agonist, BIM-23206, together with the highly selective SSTR2 agonist, BIM-23120, which displays similar monospecificity for SSTR2 subtype. Combination of these compounds resulted in an attenuation of the selective effects exerted on both [3H]thy incorporation and cell number by either agonist alone. Moreover, the preferential SSTR5 analog BIM-23206 completely counteracted the suppressive activity of BIM-23120 alone on [3H]thy incorporation and cell proliferation.
Taken together, these data show that TT cell line proliferative activity can be reduced by SSTR2-selective agonists, but not by a SSTR5 agonist, and that an SSTR5 agonist can prevent SSTR2-mediated antiproliferative effects. This evidence suggests that SSTR2 and 5 promote different effects on TT cell growth, and demonstrate that interaction and balance between distinct SSTRs can influence cell growth rate. However, the finding that SSTR5 activation reduces the antiproliferative activity mediated by SSTR2 differs from results in other tissues (4, 27, 28, 31) and may suggest tissue-specific differences in the function of SSTR subtypes 2 and 5. The human TT cell line is characterized by the loss of expression of the tumor suppressor gene p53 and a genetic mutation involving exon 11 of the Ret proto-oncogene (14). It cannot be excluded that alterations in cell cycle regulatory pathways in TT cells may be responsible for the unexpected actions exerted by SSTR5 on cell growth regulation. However, additional studies need to be considered to clarify this point. Furthermore, to investigate the effects of different SRIF analogs on TT cell proliferation, it could be of considerable interest to study their action on TT cell xenograft tumors in nude mice.
Hetero and homodimeric interactions between subtypes of the opiate (32) and SRIF (33) receptor families have also been recently demonstrated by other investigators. Interestingly, studies in cultured pituitary adenoma cells have demonstrated that SSTR subtypes 2 and 5 act synergistically in the suppression of GH and PRL secretion (34, 35). To our knowledge, this is the first demonstration that SSTR subytpe 2 and 5, can act antagonistically in regulating cell growth. These findings suggest not only tissue-specific functions, but also tissue-specific interactions between the two receptors. Such diverse interactions between receptor subtypes may prove to be one of the mechanisms by which a seemingly ubiquitous hormone such as SRIF with widespread receptor distribution can achieve functional selectivity in different tissues and physiological states. Clearly, this is an area requiring and deserving much additional study.
In conclusion, our data show that SSTR2 and 5 preferential agonists exert differential effects on proliferation of human medullary thyroid TT cell line in vitro, according to their specific SSTR selectivity. Furthermore, in these cells, we have provided the first demonstration of an antagonistic functional interaction between two SSTR subtypes. The study provides strong evidence for a key inhibitory role of SSTR2 on MTC cell proliferation, at least in TT cellular model system. This finding demonstrates the potential that analogs with enhanced SSTR2 affinity and selectivity may have as antiproliferative agents in MTC treatment.
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Footnotes |
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Received November 21, 2000.
Revised January 11, 2001.
Accepted January 29, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-2b and octreotide. Cancer. 78:1114–1118.[CrossRef][Medline]
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