Effect of bombesin infused intrapancreatically on glucagon and insulin secretion

416

228

Bombesin is shown to be a potent mitogen for Swiss 3T3 cells. At nanomolar concentrations the peptide markedly enhances the ability of fresh serum to stimulate DNA synthesis in confluent and quiescent cultures of these cells. In the presence of a low concentration (3.5%) of serum, bombesin stimulates 3T3 cell proliferation. In serum-free medium, bombesin induces DNA synthesis in the absence of any other added growth factor; halfmaximal effect is obtained at 1 nM. The mitogenic effect of bombesin is dependent on dose and time, is mimicked by litorin, and is markedly potentiated by insulin, colchicine, platelet-derived growth factor, and fibroblast-derived growth factor. These mitogens increase the maximal response elicited by bombesin and decrease the bombesin concentration required to produce halfmaximal effect (from 1 nM to 0.3 nM). In contrast, vasopressin, phorbol esters, or cAMP increasing agents fail to enhance the maximal level of DNA synthesis induced by bombesin. Bombesin and litorin may provide useful model peptides for studies on the mechanism(s) by which extracellular ligands control cell proliferation.In recent years, a considerable number of new regulatory peptides have been identified in the brain, gastrointestinal tract, and other tissues (1-3). Bombesin, a tetradecapeptide originally isolated from frog skin (4), and bombesin-like peptides have been detected in mammalian brain (5, 6), gut (5, 7), and lung (8,9). This peptide has potent pharmacological effects on the central nervous system (10-12) and elicits the release of other peptide hormones including insulin (13,14), glucagon (13,14), gastrin (5,7,14), cholecystokinin (14), and prolactin and growth hormone (15,16). Bombesin binds to specific surface receptors in pancreatic acinar cells (17) and stimulates ion fluxes (17,18) and enzyme secretion (17,18) Recently, several reports demonstrated the presence of high concentrations of bombesin in human pulmonary tumors (19)(20)(21). This observation and the report that repeated administration of bombesin induced pancreatic hyperplasia in the rat (22) raises the possibility that bombesin could participate in the control of cell proliferation, a proposition that hitherto remained unproven. Indeed, it is difficult to obtain unambiguous evidence for a direct growth-promoting activity of bombesin in vivo because the administration of this peptide stimulates the release of many other biologically active peptides (see above) which could act as proximal effectors of the action of bombesin.Cultured cells provide a useful experimental system for elucidating the extracellular factors that control cell proliferation without the many complexities of whole animal experimentation. Many mammalian cells in culture, and Swiss 3T3 cells in particular, cease to proliferate and become arrested in the G1/ Go phase of the cell cycle when they deplete the nutrient medium of its growth-promoting activity (23). Addition of fresh serum or defined growth-promoting factors to such quiescent cells stimulates reinitiati...

mentioning

confidence: 99%

Bombesin stimulation of DNA synthesis and cell division in cultures of Swiss 3T3 cells.

Rozengurt¹,

Sinnett‐Smith²

1983

416

228

“…Sustained clinical effects could then result from the constant lowlevel secretion of a bioactive form of bombesin, such as found during infusion studies in human subjects (42,43), as well as other peptide hormones from the tumor. Once in plasma, bombesin could interact with tissue receptor sites (44), thereby mediating intracellular changes that stimulate secretion of enzymes (44)(45)(46), or affect electrical potentials (10,46), or bring about the release of other peptide hormones, such as insulin (47,48), glucagon (48), gastrin (9,10,42,43,49), and prolactin and GH (50). With the growing evidence of ectopic secretion of peptides by SCC and other neoplasms (6,7,11), we suggest that bombesin should be considered among the various peptides causing endocrinologic abnormalities in patients with lung tumors.…”

Section: Discussionmentioning

confidence: 99%

Human lung small-cell carcinoma contains bombesin.

Erisman¹,

Linnoila²,

Hernández³

et al. 1982

144

The presence of immunoreactive bombesin in a human lung small-cell carcinoma grown in nude mice was established by several criteria: (i) Radioimmunoassay of tissue extracts for bombesin revealed approximately 6.5 pmol/g of tissue; (ii) bombesin was found in 12-14% of the tumor cells by immunohistochemical localization; (iii) gel filtration ofsmall-cell carcinoma extract on Sephadex G-75 and Bio-Gel P-4 gave only a single peak ofimmunoreactivity, which occurred at the elution volume ofbombesin; and (iv) reverse-phase HPLC of acid-solubilized extracts separated the immunoreactive material into three discrete peaks, one of which eluted with a retention time identical to that of synthetic bombesin. Small oat-cell carcinoma accounts for 10-25% of identifiable human lung cancers (1). This neoplasm is characterized by a rapid growth rate and a propensity to metastasize (1) and is frequently a source for "ectopic" hormone production (1-7). Many of the clinical symptoms manifested by patients with small-cell carcinoma (SCC) can be attributed to increased levels ofectopic hormones (5-7). For example, the syndrome of inappropriate secretion of antidiuretic hormone is apparently due to [Arg]vasopressin (5,6,8), whereas Cushing syndrome is considered to be caused by ectopic adrenocorticotropin (ACTH) formation and secretion, which is nonsuppressible by dexamethasone (3, 5, 7). Other symptoms may be due to the presence ofpresently unknown or undiscovered peptide hormones. In this regard, bombesin, a tetradecapeptide from anuran skin, elicits numerous physiological and pharmacological responses (9, 10) that resemble some of the clinical symptoms observed for SCC.(5, 11). Bombesin-like immunoreactivity was detected in numerous mammalian tissues (12-20), including human fetal and neonatal lung, but is apparently absent from adult lung (21). Because many immunological and enzymological changes that appear in tumors resemble those normally associated with fetal tissues, it seemed reasonable to evaluate the presence of bombesin in a lung neoplasm noted for ectopic hormone production. Bombesin in a human lung SCC grown in nude mice was demonstrated by (i) immunohistochemical localization of this peptide in the tumor, (ii) its quantitation in extracts by radioimmunoassay, and (iii) analysis by gel-filtration chromatography and reverse-phase HPLC. MATERIALS AND METHODSTumor. A SCC resected from a 51-year-old man with few apparent clinical endocrinopathies was propagated subcutaneously in athymic (nude) mice by Reid et al. (22) and generously supplied by G. Sato (University of California, San Diego). Tumors from two separate passages were analyzed separately. The tumors, 8.71 and 6.36 g wet weight, were removed and sectioned for histology, and the remainders of each were minced at 10C. They were homogenized in 5 ml of ice-cold 0.01 M sodium phosphate buffer, pH 6.8, containing 1 mM phenylmethylsulfonyl fluoride. The homogenate was slowly added to 25 ml of boiling water, boiled 30 min, and cooled on ice; then formic acid was ad...

“…Bombesin and related peptides such as gastrin-releasing peptide actuate a wide range of biological processes, including smooth muscle contraction, release of gastrointestinal hormones, and enzyme secretion from the pancreas (26)(27)(28)(29)(30). In particular, bombesin is an autocrine growth factor for small-cell lung carcinoma cells, which express high-affinity bombesin receptors (31)(32)(33)(34).…”

Section: Methodsmentioning

confidence: 99%

Creation and functional screening of a multi-usepeptide library.

Jayawickreme

Graminski

Quillan

et al. 1994

One of the most striking aspects of the GCR family is the sheer number of structures which serve as ligands. At a minimum the range includes photons (with a retinal cofactor), odorants, carbohydrates, lipids, and peptides. The peptides are of particular interest to neurobiology and endocrinology because they encompass many of the neurotransmitters, neuromodulators, and hormones. As a result, we have been interested in applying the recently described synthetic peptide libraries (2-5), which offer diverse peptides to investigations of GCR function.