The cholecystokinin2-receptor mediates calcitonin secretion, gene expression, and proliferation in the human medullary thyroid carcinoma cell line, TT.
Gastrin-induced release of calcitonin from medullary thyroid carcinomas (MTC) is based on the expression of the cholecystokinin(2)-receptor (CCK(2)R) in these tumors. Recently, we have shown that the CCK(2)R is expressed not only in MTC but also in C-cells within the normal thyroid gland. The functions of the CCK(2)R in MTC and C-cells are largely unknown. We therefore explored the effects of gastrin-induced CCK(2)R stimulation in the highly differentiated MTC cell line, TT. CCK(2)R expression in TT-cells is detectable by RT-PCR as well as immunocytochemistry. Stimulation of the CCK(2)R by gastrin induces immediate release of calcitonin from TT-cells. Moreover, quantitative (LightCycler) RT-PCR demonstrates that gastrin stimulates transcription of the calcitonin and chromogranin A genes in TT-cells. TT-cell proliferation, assessed by counting of viable cells and (3)H-thymidine uptake, is markedly increased by gastrin. This effect is inhibited by the CCK(2)R-specific antagonist L-365,260. Our findings suggest physiological functions for the CCK(2)R in calcitonin-secretion and gene expression as well as a pathophysiological role in MTC proliferation. CCK(2)R antagonists might have therapeutic potential in these tumors.
Bläker
Michael
M
Medizinische Klinik I, Zentrum für Innere Medizin, Universitätsklinikum Hamburg-Eppendorf, Martinistrabetae 52, 20246 Hamburg, Germany. blaeker@uke.uni-hamburg.de
Arrenberg
Philomena
P
Stange
Inke
I
Schulz
Martina
M
Burghardt
Sylvia
S
Michaelis
Hanna
H
Pace
Andrea
A
Greten
Heiner
H
von Schrenck
Tammo
T
de Weerth
Andreas
A
D002116:Calcitonin / Q000235:genetics / Q000378:metabolism*; D018276:Carcinoma, Medullary / Q000235:genetics / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D053379:Chromogranin A; D002864:Chromogranins / Q000235:genetics / Q000378:metabolism; D005755:Gastrins / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D043887:Receptor, Cholecystokinin B / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
D053379:Chromogranin A; D002864:Chromogranins; D005755:Gastrins; D043887:Receptor, Cholecystokinin B; D002116:Calcitonin