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PubMedDate not supplied

Specific pancreatic enzymes activate macrophages to produce tumor necrosis factor-alpha: role of nuclear factor kappa B and inhibitory kappa B proteins.

The triggering events by which mononuclear cells throughout the body are induced to produce large amounts of cytokines during acute pancreatitis are unclear. However, recent work in our laboratory demonstrated that three specific pancreatic enzymes (elastase, carboxypeptidase A, and lipase) induced dramatic tumor necrosis factor-alpha (TNF-alpha) protein production from macrophages, whereas all others could not. This series of experiments was designed to examine the second messenger system by which this occurs. The rat macrophage cell line NR8383 was incubated for 3 hours with elastase, carboxypeptidase A, lipase, trypsin, or lipopolysaccharide (positive control). Activation of nuclear factor kappa B (NF-kappa B) was demonstrated by electrophoretic mobility shift assay, presence of inhibitory kappa B alpha and beta (I kappa B-alpha and I kappa B-beta) by Western blot analysis, and TNF-alpha protein production by enzyme-linked immunosorbent assay. Elastase, carboxypeptidase A, and lipase induced degradation of I kappa B-beta (but not I kappa B-alpha), activation of NF-kappa B, and production of TNF-alpha protein, whereas inhibition of I kappa B with pyrrolidine dithiocarbamate attenuated this response. Trypsin was unable to elicit any of these responses. Macrophages can be induced by specific activated pancreatic enzymes-elastase, carboxypeptidase A, and lipase-to produce TNF-alpha. This process is dependent on I kappa B-beta degradation and NF- kappa B activation, suggesting that these enzymes trigger this second messenger system through specific membrane-bound receptors.

Acute Disease↗
PubMed1999

Gonadotropin-releasing hormone receptor concentration differentially regulates intracellular signaling pathways in GGH3 cells.

Pituitary cell lines (GGH3) expressing the GnRH receptor (GnRHR) were used to investigate the effect of GnRHR concentration on the ability of a GnRH agonist to activate second messenger systems. Four different strategies were utilized to generate cells expressing functionally different concentrations of receptors: (1) transient transfection with different concentrations of wild type GnRHR into GH3 cells, (2) utilization of two cell lines derived from a common stably transfected line expressing high (4,209 +/- 535 receptors/cell) or low (1,031 +/- 36 receptors/cell) concentrations of GnRHR, (3) co-incubation of GGH3-1' cells with a GnRH agonist (Buserelin) and a GnRH antagonist to compete for binding sites, and (4) photo-affinity binding to GnRHR with a GnRH antagonist to change effective receptor concentration. A range of receptor concentrations (1,000-8,000 receptors/cell) were generated by these techniques. Inositol phosphate (IP) and cAMP accumulation were quantified to assess the effect of receptor concentration on receptor-effector coupling. Under all four paradigms, the efficacy and potency of Buserelin stimulated IP production was dependent on receptor concentration. In contrast, Buserelin stimulated cAMP release was relatively unchanged at varying concentrations of GnRHR. This suggests that the cellular concentration of GnRHR affects the induction of cell signaling pathways. These results demonstrate that a single ligand-receptor-complex can differentially activate second messenger systems and present a mechanism by which multiple physiological endpoints can be differentially regulated by a single hormone/receptor interaction.

Animals↗
PubMed1998

Mechanisms regulating prostaglandin F2 alpha secretion from the bovine endometrium.

The mechanism that regulates luteolytic PGF2 alpha secretion as stimulated by oxytocin is thought to involve induction of the inositol (1,4,5)-trisphosphate-diacylglycerol second messenger system, which mobilizes intracellular calcium and activates protein kinase C. In Experiment 1, endometrial explants taken from heifers on d 18.5 to 19.5 postestrus had increased PGF2 alpha secretion after treatment with 1 microM calcium ionophore A23187 to increase intracellular calcium, 100 nM phorbol 12-myristate 13-acetate to activate protein kinase C, and 100 nM oxytocin. The stimulatory effects of oxytocin and calcium ionophore A23187 plus phorbol 12-myristate 13-acetate did not differ from each other. In Experiment 2, endometrial explants taken from cows on d 18.5 to 19.5 postestrus had increased PGF2 alpha secretion after treatment with 0.2 and 2 microM thapsigargin to mobilize intracellular calcium that was sensitive to inositol (1,4,5)-trisphosphate. Secretion of PGF2 alpha was also increased by 100 nM oxytocin and was influenced by the interaction of thapsigargin and oxytocin such that 100 nM oxytocin did not further increase the secretion of PGF2 alpha in the presence of 2 microM thapsigargin. In Experiment 3, 100 nM oxytocin stimulated greater production of inositol trisphosphate and total inositol phosphates in the endometrium of cyclic cows than in the endometrium of pregnant cows on d 16.5 to 17.0 postestrus, although luteolysis was not yet initiated in the cyclic cows. These results are consistent with the hypothesis that the activation of the inositol (1,4,5)-trisphosphate-diacylglycerol second messenger system by oxytocin is involved in the stimulation of PGF2 alpha secretion from the endometrium during late diestrus in cows.

Animals↗
PubMed1988

Effects of nitrovasodilators, endothelium-dependent vasodilators, and atrial peptides on cGMP.

The interactions of the nitrovasodilators, endothelium-dependent vasodilators, and atrial peptides with cGMP synthesis have proved to be useful and important leads to the functions of cGMP and signal transduction mechanisms. Although considerable progress has been made, many important questions remain to be answered. Nevertheless, the guanylate cyclase-cGMP system clearly represents an important second-messenger system that mediates the effects of numerous agents.

Atrial Natriuretic Factor↗
PubMed1996

Reduction of cerebellar GABAA responses by interleukin-1 (IL-1) through an indomethacin insensitive mechanism.

Recently, a role of IL-1 in the central nervous system has been described, principally a fever-inducing effect in the hypothalamus through a prostaglandin second messenger system. IL-1 has also been shown to potentiate gamma-aminobutyric acid (GABAA) responses in embryonic chick neurones. This study describes the investigation of the effect of IL-1 on GABAA responses within the in vitro rat cerebellar slice, a preparation containing intact neuronal circuitry. Stimulation of the area of passage of paralleled fibres produced a pure GABAA inhibition of the spontaneous firing of Purkinje cells. 5 and 10 ng/ml IL-1 produced a reduction in the duration of inhibition 10 min after beginning perfusion of IL-1. This effect reversed within 15 min of washing out the IL-1. 10 ng/ml IL-1 also reduced the effects of exogenously-applied GABA (0.1 mM) with the same time course. In the presence of 1 uM indomethacin, there was no change in the effect of the IL-1. It can therefore be concluded that the reduction in cerebellar GABAA responses by IL-1 is not mediated by the indomethacin-sensitive prostaglandin second messenger system.

Animals↗
PubMed1995

Low CO2 stimulates inositol phosphate turnover and increased inositol 1,4,5-trisphosphate levels in piglet cerebral microvascular smooth muscle cells.

In contrast to hypercapnic dilation, hypocapnia-induced cerebral vasoconstriction does not involve prostanoids in newborn pigs. The hypothesis that increased pH or decreased CO2 tension increases inositol phosphate turnover in piglet cerebral microvascular smooth muscle (SM) cells was addressed to begin to assess the possibility that this second-messenger system is involved in hypocapnia-induced cerebral vasoconstriction. Cerebral microvascular SM cells in primary culture prelabeled with [3H]-myoinositol were stimulated for 30 sec with artificial cerebrospinal fluid of increased or normal pH, (7.80 vs 7.40), constant PCO2 36 mm Hg. Following extraction from cells, radiolabeled inositol phosphates were separated by HPLC. These metabolic alkalosis studies were repeated using an inositol 1,4,5-trisphosphate (Ins[1,4,5]P3 protein-binding assay (PBA). Respiratory alkalosis using aCSF with pH 7.60, PCO2 20 mm Hg versus control pH 7.40, PCO2 36 mm Hg was similarly tested with PBS measurement of Ins(1,4,5)P3. aCSFs of control pH 7.40, and PCO2s of 70, 36, or 25 mm Hg were studied both by [3H]-myoinositol (HPLC) and PBA to further determine the importance of CO2 tension, in the presence of fixed pH, on Ins(1,4,5)P3 production. When PCO2 was constant, inositol phosphate turnover (as measured by [3H]-Ins[1,4,5]P3 accumulation) increased when pH was increased from 7.40 to 7.80 at 30 sec of stimulation. Mean [3H]-Ins(1,4,5)P3 accumulation at pHs of 7.40 and 7.80, constant PCO2 of 36 mm Hg, were 2.9 +/- 0.7 and 4.1 +/- 0.8 cpm/micrograms protein, respectively. Ins(1,4,5)P3 levels for pH of 7.40 or 7.80 and constant PCO2 of 36 mm Hg, were 25.4 +/- 1.8 and 38 +/- 8 pmol/well, respectively, by PBA. Respiratory alkalosis also increased Ins(1,4,5)P3 levels. For pH of 7.40, PCO2 36 mm Hg and pH 7.60, PCO2 20 mm Hg, Ins(1,4,5)P3 levels were 37.6 +/- 16 and 64.1 +/- 25 pmol/well, respectively. Decreasing CO2 tension (from 70 mm Hg to 25 mm Hg) in the presence of fixed pH 7.40 failed to increase Ins(1,4,5)P3 levels. The present data demonstrate that decreased CO2 tension stimulates an increase in Ins(1,4,5)P3 production in piglet cerebral microvascular smooth muscle cells. Increasing pH via lower PCO2 increases the level of Ins(1,4,5)P3 even more than increasing pH with fixed base, but extracellular pH appears to be important since decreased PCO2 without changing extracellular pH had no effect. We conclude that the inositol phosphate second messenger system in cerebral microvascular smooth muscle responds appropriately to acute alkalosis to be involved in hypocapnia-induced cerebral vasoconstriction.

Alkalosis, Respiratory↗
PubMed1990

Growth factors and oncogenes in breast cancer.

The growth of normal breast epithelial cells is regulated by a complex interacting system of polypeptide factors and by steroid hormones. The cells respond to these factors through receptors which generate mitogenic and other intracellular signals. These second messengers provoke complex responses which may ultimately result in DNA replication and cell division. A comparison of normal cells and tumour cells, either in culture or from primary tumour biopsies, has revealed differences in growth factor and growth factor receptor expression. Such changes may represent aspects of the process of malignant transformation. In addition some evidence suggests that changes in second messenger systems may also occur. Finally several changes in nuclear oncogenes have been observed in breast cancers. It has been proposed that changes in the nuclear oncogenes, perhaps involving the loss of function of tumour suppressor genes, may allow cells to enter the cell cycle. Changes in growth factors, their receptors or intracellular second messenger systems may stimulate unregulated growth. The combination of these events provide a model for the process of carcinogenesis.

Breast Neoplasms↗
PubMed1994

[Roles of tyrosine phosphorylation in the proliferation of leukemic hematopoietic stem cells--analysis using a tyrosine phosphatase inhibitor].

I investigated the effects of a tyrosine phosphatase inhibitor, orthovanadate, on the proliferation of normal and CML hematopoietic progenitor cells stimulated by different colony stimulating factors. Orthovanadate decreased CFU-GM colony formation from normal bone marrow cells stimulated by IL-3 and GM-CSF in a dose dependent manner, except for G-CSF. But, BFU-E colony formation was not affected by the treatment with orthovanadate. In CML cells, CFU-GM colony formation was relatively more resistant to orthovanadate than that in normal bone marrow cells and orthovanadate, surprisingly, increased BFU-E colony formation. Western blot analysis showed that preincubation of CML cells with orthovanadate resulted in the enhancement of tyrosine-phosphorylation of p65 mainly, when stimulated with EPO. These results suggest that the second messenger system of IL-3, G-CSF, GM-CSF, and EPO in progenitor cells in CML is different from that in normal progenitor cells and that there is big difference in the second messenger system between myeloid and erythroid progenitor cells in CML cells.

Bone Marrow Cells↗
PubMedDate not supplied

Intrastriatal infusion of amiloride increases rotations in 6-OHDA lesioned rats and "down-regulates" D2 receptors in the striatum and 5-HT2A receptors in the cortex.

Intrastriatal infusion of amiloride and 12-0-tetradeconoyl phorbol-13-acetate (TPA) in 6-OHDA lesioned rats increased the apomorphine (APO)-induced rotation. This behavioral effect occurred in the presence of a decrease in the density and an increase in the affinity of D2 dopamine receptors in the striatum. There was an associated decrease in the number of 5-HT2A receptors labelled with ketanserin in the cortex on the side of infusion. These results suggest that the inositol second-messenger system may be involved in the regulation of D2-dopamine receptors in the striatum and dopamine mediated behavior in the 6-OHDA lesioned rats. They also indicate a possible role for the inositol second messenger system in the regulation of 5-HT2A receptors.

Amiloride↗
PubMed1992

Purinergic stimulation of cell division and differentiation: mechanisms and pharmacological implications.

Extracellular purine nucleosides and nucleotides in micromolar concentrations stimulate proliferation of a variety of cell types in vitro and in vivo. As well they act synergistically with NGF to stimulate neurite outgrowth from PC12 cells. A variety of purine nucleosides and deoxyribonucleosides promote cell proliferation and increase intracellular cAMP. Their activities are inhibited by adenosine A2 receptor antagonists. Only adenosine interacts with the A2 receptor. We propose that the other nucleosides and deoxyribonucleosides inhibit extracellular adenosine deaminase, thereby increasing the extracellular concentration of adenosine. The nucleotides apparently act by stimulating P2y receptors coupled to inositol phosphate metabolism. We propose that the nucleosides and nucleotides act synergistically with other growth factors because each has distinct but complementary second messenger systems. If our hypotheses are correct, it should prove possible to modulate the growth and morphogenesis in several cell types using drugs that inhibit or stimulate adenosine A2 or purine P2y receptor agonists or the second messenger systems coupled to these receptors.

Animals↗
PubMed1990

Inhibition of growth of established human glioma cell lines by modulators of the protein kinase-C system.

The protein kinase-C (PKC) second messenger system contributes to regulation of cell growth and differentiation. This study was undertaken to examine the effects of modulators of the PKC enzyme system on the state of differentiation and proliferation rates of human gliomas in vitro. The administration of the PKC-activating phorbol esters 4-beta-phorbol-12,13-dibutyrate (PDB) and phorbol-12-myristate-13-acetate (PMA) resulted in a dose-related inhibition of growth of human glioma cell lines in vitro as measured by 3H-thymidine uptake. The synthetic nonphorbol PKC activator (SC-9) produced an even more pronounced decrease of 3H-thymidine uptake. Diacylglycerol, an endogenous activator of the system, applied externally, transiently decreased the proliferation, in concordance with its short-lived existence in vivo. Conversely, the administration of 4-alpha-phorbol-12,13-didecanoate (alpha-PDD), a phorbol ester that binds but does not activate the enzyme, had no effect on the proliferation rate. At the dosages that maximally decreased proliferation, there was no evidence of direct glioma cell lysis induced by these agents as measured by a chromium-release assay. Immunocytochemical analysis and cytofluorometric measurement of glial fibrillary acidic protein (GFAP) staining in the treated cultures revealed an increase in GFAP staining over control cultures. In contrast to the response of glioma cells, nonmalignant human adult astrocytes treated with the PKC activators responded by increasing their proliferation rate. The authors postulate that the diametrically opposed effects of PKC activators on nonmalignant astrocytes versus glioma growth may be due to a high intrinsic PKC activity in glioma cells, with resultant down-regulation of enzyme activity following the administration of the pharmacological activators.

Astrocytes↗
PubMed1997

The expression of a cloned Drosophila octopamine/tyramine receptor in Xenopus oocytes.

The expression of a cloned Drosophila octopamine/tyramine receptor (OctyR99AB) is described in Xenopus oocytes. Agonist stimulation of OctyR99AB receptors increased intracellular Ca2+ levels monitored as changes in the endogenous inward Ca2+-dependent chloride current. The receptor is preferentially sensitive to biogenic amines with a single hydroxyl on the aromatic ring. The G-protein, Galphai, appears to be involved in the coupling of the receptor to the production of intracellular calcium signals, since the effect is pertussis-toxin sensitive and is blocked or substantially reduced in antisense knockout experiments using oligonucleotides directed against Galphai but not by those directed against Galphao, Galphaq and Galpha11. The increase in intracellular calcium levels induced by activation of the OctyR99AB receptor can potentiate the ability of activation of a co-expressed beta2-adrenergic receptor to increase oocyte cyclic AMP levels. A comparison of the pharmacological coupling of OctyR99AB to different second messenger systems when expressed in Xenopus oocytes with previous studies on the expression of the receptor in a Chinese hamster ovary cell line suggests that the property of agonist-specific coupling of the receptor to different second messenger systems may be cell-specific, depending upon the G-protein environment of any particular cell type.

Animals↗
PubMed1987

Forskolin and phorbol esters reduce the same potassium conductance of mouse neurons in culture.

Second messenger systems may modulate neuronal activity through protein phosphorylation. However, interactions between two major second messenger pathways, the cyclic AMP and phosphatidylinositol systems, are not well understood. The effects of activators of cyclic AMP-dependent protein kinase and protein kinase C on resting membrane properties, action potentials, and currents recorded from mouse dorsal root ganglion neurons and cerebral hemisphere neurons grown in primary dissociated cell culture were investigated. Neither forskolin (FOR) nor phorbol 12,13-dibutyrate (PDBu) altered resting membrane properties but both increased the duration of calcium-dependent action potentials in both central and peripheral neurons. By means of the single-electrode voltage clamp technique, FOR and PDBu were shown to decrease the same voltage-dependent potassium conductance. This suggests that two independent second messenger systems may affect the same potassium conductance.

Action Potentials↗
PubMed1991

Autoradiographic analysis of second messenger and neurotransmitter system receptors in the gerbil hippocampus following transient forebrain ischemia.

Changes in second messenger and neurotransmitter system receptor ligand binding induced by transient forebrain ischemia were studied in the gerbil hippocampus. The animals were allowed variable periods of recovery ranging from 2 h to 7 days after 5-min bilateral carotid artery occlusion. The binding of second messenger systems ([3H]inositol 1,4,5-trisphosphate ([3H]IP3)to inositol 1,4,5-triphosphate, [3H]forskolin to adenylate cyclase and [3H]phorbol 12,13-dibutylate to protein kinase C) and neurotransmitter receptor systems ([3H]PN200-110 to L-type calcium channels. [3H]N6-cyclohexyl-adenosine to adenosine A1 and [3H]quinuclidinyl benzilate to muscarinic cholinergic receptor) were assayed using quantitative autoradiography. In the CA1 subfield, 2 h after ischemia, [3H]IP3, [3H]forskolin, and [3H]quinuclidinyl benzilate binding activities significantly decreased by 25, 17 and 13%, respectively, though no morphological abnormalities were obvious. Six hours after ischemia, the [3H]phorbol 12,13-dibutylate binding activity in the stratum oriens of the CA1 subfield increased by 15%. One day after ischemia, [3H]PN200-110 binding activity in this subfield decreased by 26%, and 7 days after ischemia, [3H]phorbol 12,13-dibutylate and [3H]N6-cyclohexyl-adenosine receptor binding activities decreased in this subfield. In particular, at 7 days after ischemia, [3H]IP3 binding activity in the CA1 subfield showed a complete decline. In the CA3 subfield, [3H]PN200-110 binding activity decreased 2 days after ischemia, and [3H]IP3 and [3H]N6-cyclohexyl-adenosine binding activities decreased 7 days after ischemia. In the dentate gyrus, the structure of which remained histologically intact after ischemic insult, [3H]IP3 and [3H]forskolin binding activities decreased 7 days after ischemia. In contrast, the [3H]phorbol 12,13-dibutylate binding activity increased in the molecular layer of the dentate gyrus 7 days after ischemia. These results indicate that marked alteration of intracellular signal transduction precedes neuronal damage in the hippocampal CA1 subfield and that the histologically intact CA3 and dentate gyrus also shows modulated neuronal transmission after ischemia.

Adenosine↗
PubMed1989

Rescue of the Li+-induced delay of embryonic myogenesis in vitro by added inositol.

Signaling between embryonic myoblasts to coordinate gene expression is part of normal skeletal muscle development in the embryo. An unanswered question is the nature of the second messengers carrying the information to the nucleus. We have investigated the cell membrane events associated with the binding of prostaglandin to a transient receptor on the embryonic chick myoblast membrane in vitro. The membrane events include a transient change in membrane order seen by electron paramagnetic resonance (EPR), a change in cell-cell adhesion, a rapid decrease in membrane permeability and fusion of the membrane bilayers. The addition of 20 mM Li+, an inhibitor of inositol phosphate phosphatase, perturbed the transient change in membrane order and delayed the change in cell-cell adhesion and conductivity for 2-6 h. Other alkali metal ions had no such effects. The addition of inositol to the culture medium in the continued presence of Li+ restored the normal timing of the two latter events. We interpret this as evidence for an inositol phosphate second messenger system which might connect the activation of the prostaglandin receptor with the change in cell-cell adhesion, the changes in membrane conductivity and perhaps bilayer fusion. We suggest that Li+, by blocking the regeneration of polyphosphatidylinositol from inositol phosphate, reduced the efficiency of the second messenger system such that further differentiation of the myoblast membrane was delayed. The exogenous inositol provided an alternative source and membrane differentiation was unaffected.

Animals↗
PubMed1992

Proliferative response of smooth muscle cells in hypertension.

A significant increase (up to 20% from about 10% in normals) in the number of smooth muscle cells (SMC) with tetraploid DNA content was found in the media and intima of human hypertensive aorta. A similar process was detected during normal human vessel aging. It was found that SMC from normal human aorta and normotensive rat aorta, which were able to incorporate 3H-thymidine, had diminished proliferative potency and a tendency to polyploidization in primary culture. We failed to detect a similar phenomenon in SMC obtained from aorta from spontaneously hypertensive rats. It was found that 10 mumol/L of norepinephrine significantly increased (by approximately twofold) the frequency of true polyploid cells in a subculture of rat aortic SMC. The effect of norepinephrine was blocked only by simultaneous action of alpha- and beta-adrenoreceptor antagonists. SMC polyploidization was also stimulated by simultaneous application of two direct activators of the second messenger systems, forskolin and phorbol-12-myristate-13-acetate. Thus, a subpopulation of SMC prone to polyploidization exists in normal vessels, and norepinephrine may be one of the mediators of the "hypertensive" response of vessel wall SMC, which probably occurs due to the synergism of two second messenger systems.

Adult↗
PubMed1991

[Proliferation of smooth muscle cells in hypertension].

The aortic intima and media isolated from hypertensives showed a significantly larger number (up to 20%) of smooth muscle cells (SMC) with tetraploid DNA content. The similar process was shown to be also a part of normal human vessel maturation. Normotensive human and rat aortic SMCs were found to accumulate 3H-thymidine, have a lower proliferative ability and they were apt to polyploidize in the primary culture. Such a population could not be detected in the aorta of spontaneously hypertensive rats. It was ascertained that 10 microM of noradrenaline significantly increased (approximately by 2 times) the occurrence of true polyploid cells in the rat aortic SMC subculture. The effect of noradrenaline was blocked by the concomitant effects of alpha- and beta-adrenoreceptor antagonists. SMC polyploidization was also stimulated by the simultaneously use of the direct activators of second messenger systems forskolin and phorbol-12-myristate-13-acetate. Thus, the SMC subpopulation that is apt to polyploidize exists in normal vessels and noradrenaline may be one of the mediators of a response of the vascular wall SMC, which seems to occur due to the synergism of two second messenger systems.

Animals↗
PubMed1994

Calcitonin stimulates growth of human prostate cancer cells through receptor-mediated increase in cyclic adenosine 3',5'-monophosphates and cytoplasmic Ca2+ transients.

Our recent study has shown that a calcitonin (CT)-like immunoreactive substance(s) is secreted by cultured prostate cells, and secretion of this material is significantly higher in malignant than in benign prostate cells. To test the hypothesis that prostatic CT may serve as a paracrine/neuroendocrine factor, the present study investigated for the presence of CT receptors in the prostate gland. Signal transduction mechanisms activated by CT were examined, and the study also tested its effects on prostate cell proliferation, as assessed by [3H]thymidine incorporation. The results show that high affinity binding sites for [125I]salmon CT were present in plasma membrane fractions of human prostate tissue specimens and the prostate cancer LnCaP cell line. The maximal binding for CT receptors was 564 +/- 163 fmol/mg protein, and the apparent dissociation constant (Kd) was 2.89 +/- 0.58 nM. CT induced a dose-dependent increase in cAMP generation in LnCaP cells. The effect of CT on cytoplasmic Ca2+ transients of LnCaP cells was examined by videofluoromicroscopy. CT (100 nM) induced a rapid and sharp increase in cytoplasmic Ca2+ concentrations in LnCaP cells. The CT-induced increase in cytoplasmic Ca2+ transients appeared to be biphasic (spike and plateau), and this increase was 4- to 10-fold during the initial phase. The profile of this response is characteristic of the activated Ca2+/phospholipid second messenger system. CT also caused a dose-dependent increase in [3H]thymidine incorporation by LnCaP cells. These results suggest that a locally secreted CT-like peptide(s) induces mitogenic responses in prostate cancer cells. This action seems to be mediated through activation of signaling mechanisms, leading to the accumulation of two different second messengers, cAMP and calcium. Activation of dual second messenger systems by CT receptors suggests that the peptide hormone may play an important role in rapidly growing cell populations during the process of tumor formation.

Adenocarcinoma↗