Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

After therapeutic hormone deprivation, prostate cancer cells often develop androgen-insensitive growth through mechanisms thus far undefined. Neuropeptides have been previously implicated as growth factors in some prostate cancers. Here, we demonstrate that androgen-sensitive LNCaP human prostate cancer cells produce and secrete neurotensin following androgen withdrawal. We show that while LNCaP cells express the neurotensin receptor, only androgen-deprived cells exhibit a growth response to exogenous neurotensin. We further demonstrate that androgen-stimulated cells may be refractory to exogenous neurotensin due to androgen induction of a metalloprotease active toward neurotensin. Thus, prostate cancer cells deprived of androgen develop an alternative autocrine growth mechanism involving neurotensin.
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PMID:Neurotensin is an autocrine trophic factor stimulated by androgen withdrawal in human prostate cancer. 819 17

The formation and processing of neurotensin (NT) by three prostate cancer cell lines was investigated. Neurotensin (NT) immunoreactivity was detected in conditioned media and extracts of LNCaP cells. Using HPLC techniques, the immunoreactivity extracted from LNCaP cells coeluted with synthetic NT standard. Metalloendopeptidase 3.4.24.15 activity was detected in PC-3, DU-145 and LNCaP cells, whereas high levels of neutral endopeptidase 3.4.24.1 1 activity was detected only in LNCaP cells. NT was relatively stable when incubated with PC-3 or D-145 cells but was rapidly degraded by LNCaP cells to NT1-11 and NT1-10. Phosphoramidon inhibited the metabolism of NT by LNCaP cells. These data suggest that NT is present in and metabolized by LNCaP cellular enzymes.
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PMID:Neurotensin is metabolized by endogenous proteases in prostate cancer cell lines. 949 57

A human prostate cancer cell line (PC3) with abundant neurotensin (NT) receptors was used to demonstrate that NT potentiated 3',5'-cyclic adenosine monophate (cAMP) accumulation in response to a variety of stimuli, including both direct forskolin (F) and indirect (prostaglandin, (PGE2), isoproterenol (ISO) and cholera toxin (CTx)) activators of adenylyl cyclase. Several mechanisms were investigated and our results indicated an effect on the rate of cAMP formation and not on degradation or extrusion. For each stimulus, NT enhanced efficacy without altering EC50. The effect of NT did not involve stimulatory G-protein (Gs)-activation or interference with a tonic inhibitory G-protein (Gi)-mediated inhibition. A similar response was obtained when NT was added with the stimulus or given as a two minute pulse which was removed prior to addition of stimulus. The potentiating activity disappeared with a t1,2 of approximately 15 min. NT transiently elevated cellular [Ca2+]i and its effects on cAMP could be mimicked by [Ca2+]i-elevating agents (uridine triphosphate (UTP), thapsigargin and ionomycin). Buffering cellular [Ca2+]i with 1,2-bis (2-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester (BAPTA-AM) inhibited cAMP responses to ISO and F in presence and absence of NT. These data support the idea that NT potentiated cAMP formation in response to a variety of stimuli by facilitating the activation of Ca2+ -dependent adenylyl cyclases.
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PMID:Neurotensin enhances agonist-induced cAMP accumulation in PC3 cells via Ca2+ -dependent adenylyl cyclase(s). 986 26

Since neurotensin is often co-stored with catecholamines and since it can excite the release of dopamine and norepinephrine, responses to this peptide might depend upon the activity of catecholaminergic systems. In this study, we used prostate cancer PC3 cells, which express neurotensin receptors and 12-adrenergic receptors, to demonstrate that neurotensin can potentiate the effects of isoproterenol on 3',5'-cyclic adenosine monophosphate (cAMP) formation and on inhibition of DNA synthesis. While neurotensin had only a slight effect on basal cAMP levels, it nearly doubled the response to isoproterenol even at maximal levels without altering potency. Neurotensin increased the rate of cAMP accumulation and the steady-state level achieved. Consistent with the known antimitogenic action of dibutyryl-cAMP in PC3 cells, isoproterenol was found to inhibit DNA synthesis concentration-dependently, measured using [3H]thymidine. Neurotensin enhanced DNA synthesis when given alone. However, it inhibited DNA synthesis when given with a threshold level of isoproterenol, which by itself had no significant effect. These results, demonstrating cross-talk in the neurotensin and beta-adrenergic signaling pathways, suggest that there may be other physiologic instances of similar interactions between neurotensin and catecholamines.
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PMID:Synergistic effects of neurotensin and beta-adrenergic agonist on 3,5-cyclic adenosine monophosphate accumulation and DNA synthesis in prostate cancer PC3 cells. 1035 60

The expressed sequence tag (EST) databases are an attractive starting point for gene discovery for diseases like cancer. Validation of gene targets from these sequences (both known and novel) in cancers requires a comprehensive expression profiling. We identified from the Cancer Gene Anatomy Project database (CGAP), a hit called neurotensin receptor (NT-r) that was expressed in the pancreatic cancer cDNA libraries. Neurotensin (NT), a neuroendocrine peptide, exerts trophic effects in vivo and stimulates the growth of cancer-derived cell lines in vitro. High affinity neurotensin receptors (NT-r) are expressed in cancer-derived cell lines and in some primary tumors. To date, a comprehensive expression profile of the NT-r in diverse cancers and normal tissues has not been reported. A cancer-selective expression of NT-r, if demonstrable, may provide a basis for a diagnostic and potential therapeutic utility. We demonstrate that the NT-r is expressed in a variety of cancer-derived cell lines as well as primary tumors, but only in a select few normal tissues. The expression of NT, on the other hand, was detected in many normal tissues, but not in the cancer-derived cell lines. The NT expression however, was detected in the primary tumors. We further demonstrate that NT expression is stimulated by androgen deprivation in the prostate cancer models. These results demonstrate the usefulness of a panel of cDNA repository for rapid validation of potential cancer targets.
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PMID:Relevant genomics of neurotensin receptor in cancer. 1076 34

The bombesin/gastrin-releasing peptide (GRP) family of neuropeptides has been implicated in various in vitro and in vivo models of human malignancies including prostate cancers. It was previously shown that bombesin and/or neurotensin (NT) acts as a survival and migratory factor(s) for androgen-independent prostate cancers. However, a role in the transition from an androgen-dependent to -refractory state has not been addressed. In this study, we investigate the biological effects and signal pathways of bombesin and NT on LNCaP, a prostate cancer cell line which requires androgen for growth. We show that both neurotrophic factors can induce LNCaP growth in the absence of androgen. Concurrent transactivation of reporter genes driven by the prostate-specific antigen promoter or a promoter carrying an androgen-responsive element (ARE) indicate that growth stimulation is accompanied by androgen receptor (AR) activation. Furthermore, neurotrophic factor-induced gene activation was also present in PC3 cells transfected with the AR but not in the parental line which lacks the AR. Given that bombesin does not directly bind to the AR and is known to engage a G-protein-coupled receptor, we investigated downstream signaling events that could possibly interact with the AR pathway. We found that three nonreceptor tyrosine kinases, focal adhesion kinase (FAK), Src, and Etk/BMX play important parts in this process. Etk/Bmx activation requires FAK and Src and is critical for neurotrophic factor-induced growth, as LNCaP cells transfected with a dominant-negative Etk/BMX fail to respond to bombesin. Etk's activation requires FAK, Src, but not phosphatidylinositol 3-kinase. Likewise, bombesin-induced AR activation is inhibited by the dominant-negative mutant of either Src or FAK. Thus, in addition to defining a new G-protein pathway, this report makes the following points regarding prostate cancer. (i) Neurotrophic factors can activate the AR, thus circumventing the normal growth inhibition caused by androgen ablation. (ii) Tyrosine kinases are involved in neurotrophic factor-mediated AR activation and, as such, may serve as targets of future therapeutics, to be used in conjunction with current antihormone and antineuropeptide therapies.
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PMID:Neuropeptide-induced androgen independence in prostate cancer cells: roles of nonreceptor tyrosine kinases Etk/Bmx, Src, and focal adhesion kinase. 1171 75

Gastrointestinal (GI) hormones are chemical messengers that regulate the physiological functions of the intestine and pancreas, including secretion, motility, absorption, and digestion. In addition to these well-defined physiological effects, GI hormones can stimulate proliferation of the nonneoplastic intestinal mucosa and pancreas. Furthermore, in an analogous fashion to breast and prostate cancer, certain GI cancers possess receptors for GI hormones; growth can be altered by administration of these hormones or by blocking their respective receptors. The GI hormones that affect proliferation, either stimulatory or inhibitory, include gastrin, cholecystokinin, gastrin-releasing peptide, neurotensin, peptide YY, glucagon-like peptide-2, and somatostatin. The effects of these peptides on normal and neoplastic GI tissues will be described. Also, future perspectives and potential therapeutic implications will be discussed.
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PMID:Role of gastrointestinal hormones in the proliferation of normal and neoplastic tissues. 1457 Jul 43

Neurotensin (NT) stimulates Ca2+ release and Ca2+ influx in many cells. Its contractile effects in smooth muscle are inhibited by removal of Ca2+ and by Ca2+ channel blockers (CCBs). To better understand NT signaling in prostate cancer PC3 cells, blockers of voltage-gated and store-operated Ca2+ channels (VGCC and SOCC) were tested for effects on NT-binding and signaling. Eight chemical types of agents, including VGCC-blocker nifedipine and SOCC-blocker SKF-96365 (1-[beta-[3-(4-methoxyphenyl)-propoxy]-4-methoxyphenyl]-1H-imidazole), enhanced cellular NT binding up to 3-fold, while inhibiting (by congruent with 70%) NT-induced inositol phosphate (IP) formation. The ability to enhance NT binding correlated with the ability to inhibit NT-induced IP formation, and both effects were relatively specific for NT. Although cellular binding for beta2-adrenergic, V1a-vasopressin, and epidermal growth factor receptors was not enhanced by these drugs, bombesin receptor binding was increased approximately equal to 19% and bombesin-induced IP formation was inhibited approximately equal to 15%. One difference was that the effect on NT binding was Ca2+-independent, whereas the effect on IP formation was Ca2+-dependent (in part). The Ca2+-dependent part of the IP response seemed to involve SOCC-mediated Ca2+ influx to activate phospholipase C (PLC)delta, while the Ca2+-independent part probably involved PLCbeta. Photoaffinity labeling of the NT receptor NTR1 was enhanced in CCB-treated cells. NTR1 affinity was increased but NTR1 number and internalization were unchanged. Since CCBs did not alter NT binding to isolated cell membranes, the effects in live cells were indirect. These results suggest that CCBs exert two effects: 1) they inhibit NT-induced IP formation, perhaps by preventing Ca2+ influx-dependent activation of PLCdelta; and 2) they enhance NTR1 affinity by an unexplained Ca2+-independent mechanism.
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PMID:Ca2+ channel blockers enhance neurotensin (NT) binding and inhibit NT-induced inositol phosphate formation in prostate cancer PC3 cells. 1457 Aug 23

This study aimed to determine the mechanism(s) by which 1,4-dihydropyridine Ca2+ channel blockers (DHPs) enhance the binding of neurotensin (NT) to prostate cancer PC3 cells and inhibit NT-induced inositol phosphate formation. Earlier work indicated that these effects, which involved the G protein-coupled NT receptor NTR1, were indirect and required cellular metabolism or architecture. At the micromolar concentrations used, DHPs can block voltage-sensitive and store-operated Ca2+ channels, K+ channels, and Na+ channels, and can inhibit lipid peroxidation. By varying [Ca2+] and testing the effects of stimulators and inhibitors of Ca2+ influx and internal Ca2+ release, we determined that although DHPs may have inhibited inositol phosphate formation partly by blocking Ca2+ influx, the effect on NT binding was Ca2+-independent. By varying [K+] and [Na+], we showed that these ions did not contribute to either effect. For a series of DHPs, the activity order for effects on NTR1 function followed that for antioxidant ability. Antioxidant polyphenols (luteolin and resveratrol) mimicked the effects of DHPs and showed structural similarity to DHPs. Antioxidants with equal redox ability, but without structural similarity to DHPs (such as alpha-tocopherol, riboflavin, and N-acetyl-cysteine) were without effect. A flavoprotein oxidase inhibitor (diphenylene iodonium) and a hydroxy radical scavenger (butylated hydroxy anisole) also displayed the effects of DHPs. In conclusion, DHPs indirectly alter NTR1 function in live cells by a mechanism that depends on the drug's ability to donate hydrogen but does not simply involve sulfhydryl reduction.
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PMID:Polyphenolic antioxidants mimic the effects of 1,4-dihydropyridines on neurotensin receptor function in PC3 cells. 1471 82

Once metastatic, prostate cancer (CaP) treatment options are limited to androgen withdrawal. In this environment, the cells often develop an androgen independent state resulting in patient demise. It has been shown that during this transition, CaP cells transdifferentiate to neuroendocrine cells, which produce neuropeptides. These neuropeptides have a mitogenic effect on surrounding CaP cells. Previous observations suggest that endothelial cells may show a similar mitogenic response to neuropeptides, implicating angiogenesis in the progression of CaP. We stimulated human umbilical endothelial cells (HUVECs) with the neuropeptides bombesin and neurotensin and measured proliferation, migration, cell tube formation, and tyrosine kinase activation. In our studies, neurotensin and bombesin did not stimulate HUVEC proliferation, migration, nor tube formation. Although HUVECs express the non-receptor tyrosine kinases Fak, Src, and Etk which mediate neuropeptide signaling in CaP, they are not activated by neuropeptides in HUVECs.
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PMID:Angiogenesis is not mediated by prostate cancer neuropeptides. 1516 97


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