High affinity binding of cholecystokinin to small cell lung cancer cells (original) (raw)
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Annals of the New York Academy of Sciences, 1994
Thc incidence of carcinoma of the lung in the western world has been increasing at a dramatic rate during the last 50 years and it has become the principal cause of cancer deaths. Small cell lung cancer (SCLC), which constitutes 25% of all pulmonary cancers, follows a very aggressive clinical course despite initial sensitivity to chemotherapy and radi0therapy.l Novel therapeutic approaches are needed and they will arise, most likely, from a better understanding of the factors and intracellular events that are responsible for stimulating the rapid growth of SCLC cells.
Expression of the cholecystokinin gene in a human (small-cell) lung carcinoma cell-line
FEBS Letters, 1990
Expression of the cholecystokinin (CCK), gastrin and enkephalin A genes were studied by Northern blot analysis and a library of sequence-specific radioimmunoassays in human cell lines. The human small-cell lung carcinoma line (SCLC) U-1690 expressed moderate levels of CCK mRNA as compared to the human neuroepithelioma cell line SK-N-MC. Neither gastrin nor (pro)enkephalin A mRNAs were detectable in the U-1690 cell line. In contrast, the SCLC-line H-69 expressed Enk A but no CCK mRNA. The radioimmunoassays showed that the CCK mRNA transcript in the SCLC line U-1690 also is translated, and that preproCCK is processed into bioactive, carboxyamidated CCK peptides. Thus, the human small cell carcinoma cell line U-1690 is a useful model for studies of cell-specific CCK gene expression.
Cancer Research
Castrili, cholecystokinin (CCK), and CCK-related peptides comprise a Imimonili family characterized by an identical carboxy-terminal amino acid sequence, a domain critical for receptor binding. The addition of gastrin to small cell lung cancer (SCLC) cells causes a rapid and transient increase in the intracellular concentration of calcium i|(';r'|,i. Further more, gastrin acts as a direct growth factor through CCKn/gastrin recep tors. We report here that the expression of the mRNA coding for CCKu/ gastrin receptors correlates with the responsiveness of SCLC cells to gastrin in terms of (';r ' mobilization and stimulation of clonal growth in semisolid medium. The GLC19 SCLC cell line had no detectable expres sion of CCKn/gastrin receptor mRNA. Accordingly, gastrin (1-100 IIMIdid not cause any measurable increase in |('¡i '' |¡-In contrast, the addition of cholecystokinin residues 26â€"33(CCK-8) caused a rapid and transient increase in |< '¡r'1 ], in this cell line. CCK-8 mobilized « ;i '' in a dosedependent manner in the nanomolar range (half-maximal stimulatory concentration = 12 nvi). Furthermore, the selective CCKA antagonist CAM-1481 inhibited the increase in |(':i-'-|, induced by CCK-8 (halfmaximal inhibitory concentration = 3 n>i) in GLC19 but not in H510 cells. The selective CCKn/gastrin antagonist blocked the increase in |(;r ' |, induced by CCK-8 (half-maximal inhibitory concentration = 80 pM) in H510 but not in GLC19 cells. Thus, the effects of CCK-8 are mediated through CCKA receptors in GLC19 cells and via CCKB/gastrin receptors in H510 cells. CCK-8 markedly stimulated colony formation in GLC19 cells in a dose-dependent manner in the nanomolar range, whereas over the same concentration range, gastrin had no effect on clonal growth. CAM-1481 inhibited the CCK-stimulated colony formation in GLC19 but not in H510 cells. Our results show, for the first time, that CCKA receptors can mediate (a'' mobilization and growth in SCLC cells and that SCLC cells express two distinct functional CCK receptor subtypes.
Cancer research, 1993
Gastrin, cholecystokinin (CCK), and CCK-related peptides comprise a hormonal family characterized by an identical carboxy-terminal amino acid sequence, a domain critical for receptor binding. The addition of gastrin to small cell lung cancer (SCLC) cells causes a rapid and transient increase in the intracellular concentration of calcium ([Ca2+]i). Furthermore, gastrin acts as a direct growth factor through CCKB/gastrin receptors. We report here that the expression of the mRNA coding for CCKB/gastrin receptors correlates with the responsiveness of SCLC cells to gastrin in terms of Ca2+ mobilization and stimulation of clonal growth in semisolid medium. The GLC19 SCLC cell line had no detectable expression of CCKB/gastrin receptor mRNA. Accordingly, gastrin (1-100 nM) did not cause any measurable increase in [Ca2+]i. In contrast, the addition of cholecystokinin residues 26-33 (CCK-8) caused a rapid and transient increase in [Ca2+]i in this cell line. CCK-8 mobilized Ca2+ in a dose-depe...
Assessment of cholecystokinin 2 receptor (CCK2R) in neoplastic tissue
Oncotarget, 2016
The expression of cholecystokinin 2 receptor (CCK2R, CCKBR or gastrin receptor) has been reported on a diverse range of cancers such as colorectal, liver, lung, pancreatic, ovarian, stomach, thyroid and numerous neuroendocrine/carcinoid tumors. Some cancers of the colorectum, lung, pancreas and thyroid have been shown to overexpress CCK2R in relation to normal matched tissues of the same organ. This reported overexpression has led to the development of a number of CCK2R-ligand targeted imaging and therapeutic agents. However, no comprehensive study comparing the expression of CCK2R in multiple cancers to multiple normal tissues has been performed. Herein, we report the immunohistochemical analysis of cancer samples from gastrointestinal stromal tumor (GIST), hepatocellular carcinoma (HCC), non-small cell lung cancer (NSCLC), pancreatic adenocarcinoma, and thyroid cancer against multiple normal tissue samples from esophagus, liver, lung, pancreas, stomach, spleen and thyroid. These r...
Clinical cancer research : an official journal of the American Association for Cancer Research, 1999
The high sensitivity of pentagastrin stimulation in detecting primary or metastatic medullary thyroid cancer (MTC) suggests widespread expression of the corresponding receptor type on human MTC. Indeed, autoradiographic studies demonstrated cholecystokinin (CCK)-B/gastrin receptors not only in >90% of MTCs but in a high percentage of small cell lung cancers and potentially a variety of gastrointestinal adenocarcinomas. In a pilot study, we have demonstrated the feasibility of radiolabeled gastrin-I to target CCK-B receptor-expressing tissues in vivo in animals and patients (T. M. Behr et al., Eur. J. Nucl. Med., 25: 424-430, 1998). The aim of the present study was to systematically optimize, in a preclinical model, suitable radioligands for targeting CCK-B receptors in vivo. For this purpose, a variety of CCK/gastrin-related peptides, all having in common the COOH-terminal CCK-receptor binding tetrapeptide sequence Trp-Met-Asp-PheNH2 or derivatives thereof, were studied. They wer...
Cholecystokinin stimulates growth of human pancreatic adenocarcinoma SW1990
Digestive Diseases and Sciences, 1990
The effect of a synthetic analogue of CCK (Thr4,Nle7CCK-9) on growth of SW-1990 human pancreatic cancer was examined in two experimental models. Nude mice bearing SW-1990 pancreatic cancer xenografts were injected with CCK (5, 15, or 25μg/kg) or vehicle twice daily for 20 days. Animals were then sacrificed and tumor volume, weight, protein, and deoxyribonucleic acid (DNA) content were evaluated. SW-1990 cells were grown in vitro and the effects of CCK, secretin, vasoactive intestinal peptide (VIP), and proglumide (a CCK-receptor antagonist) on cell number and DNA synthesis were determined. The highest dose of CCK, 25 μg/kg, significantly increased tumor weight, protein content, and DNA content P<0.005). In vitro, CCK caused significant increases in cell counts of up to 47% at six days and 66% at 12 days compared to control. Graded concentrations of CCK had a biphasic effect on DNA synthesis with significant increases of up to 65% P<0.005). CCK-induced cell proliferation was inhibited by proglumide. Secretin slightly increased cancer cell growth, although not as potently as CCK. VIP or secretin in combination with CCK did not show potentiation. These results indicate that growth of some human pancreatic cancers may be influenced by gastrointestinal peptides, of which CCK is the most potent.
Comparative biodistribution of 12 111In-labelled gastrin/CCK2 receptor-targeting peptides
European Journal of Nuclear Medicine and Molecular Imaging, 2011
Purpose Cholecystokinin 2 (CCK-2) receptor overexpression has been demonstrated in various tumours such as medullary thyroid carcinomas and small-cell lung cancers. Due to this high expression, CCK-2 receptors might be suitable targets for radionuclide imaging and/or radionuclide therapy. Several CCK-2 receptor-binding radiopeptides have been developed and some have been tested in patients. Here we aimed to compare the in vivo tumour targeting properties of 12 111 Inlabelled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-conjugated gastrin/CCK2 receptor-binding peptides. Methods Two CCK8-based peptides and ten gastrin-based peptide analogues were tested. All peptides were conjugated with DOTA and labelled with 111 In. Biodistribution studies were performed in mice with subcutaneous CCK2/
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1994
The murine neuroendocrine cell line, STC-1, was found to contain 296.8 + 1.8 fmol of cholecystokinin-like immunoreactivity (CCK-LI) per mg cell protein. Immunocytochemieal stain of STC-1 cells maintained in monolayer culture indicated that CCK-LI activity was present in 93% of the cells. Analysis by reverse-phase high-performance liquid chromatography indicated that STC-1 cells contained CCK-8 and an unidentified form as the predominant storage form. However, only CCK-8 was released into the culture medium upon stimulation by various secretagogues. The release of CCK-LI from STC-1 cells was stimulated by dibutyryl cAMP, forskolin, KCI, A23187, 4/3-phorbol 12-myristate 13-acetate and luminal stimulants, e.g., sodium oleate, L-tryptophan, camostat and plaunotol. The release of CCK-LI from STC-1 cells was also stimulated by a neuropeptide, bombesin. The stimulatory effects of most of these agents were dose dependent. The stimulatory effects of dibutyryl cAMP, forskolin, and plaunotol were potentiated by 3-isobutyl-l-methyl xanthine, while that of camostat was not. The results obtained in this study indicate that the release of CCK from STC-1 cells shares the same characteristics of CCK release as from the CCK-secreting cells of the intestinal mucosa observed both in the dog and the rat in vitro and in vivo. Thus, the cellular mechanism of CCK release which appears to be cAMP-and Ca2+-dependent may be modulated by cellular protein kinase C activity. The STC-1 cell appears to be a suitable model for studying the mechanism of CCK release.