vasoactive-intestinal-peptide and Carcinoma--Squamous-Cell

We previously demonstrated that the gamma-glutamyl 16 amine derivative of vasoactive intestinal peptide (VIP) acts as structural VIP agonist with affinity and potency higher than VIP. Herein, we have evaluated the effects of VIP and gamma-Gln16-diaminopropane derivative of VIP (VIP-DAP3) on the proliferation and protection from oxidative stress induced by hydrogen peroxide (H2O2) on epidermoid carcinoma cell lines. We have found that 10(-11) M VIP-DAP3 completely antagonized the inhibition induced by H2O2 on both cell proliferation and S-phase distribution while these effects were only partially antagonized by equimolar concentrations of VIP. Moreover, both oxidative stress and intracellular lipid oxidation induced by H2O2 were reduced by VIP and completely antagonized by VIP-DAP3. Thereafter, we have found that H2O2 increased p38 kinase activity and both HSP70 and HSP27 expression. VIP and VIP-DAP3 again antagonized these effects partially or totally, respectively. H2O2 reduced the activity of extracellular signal-regulated kinases Erk-1/2 and Akt, signalling proteins involved in proliferation/survival pathways. Again VIP restored the activity of both kinases while VIP-DAP3 caused indeed an increase of their activity as compared to untreated cells. These data suggest that VIP-DAP3 has a stronger anti-oxidative activity as compared to VIP likely based on its super-agonistic binding on the putative receptor.

Topics: Antioxidants; Carcinoma, Squamous Cell; Cell Line, Tumor; Humans; MAP Kinase Signaling System; Mitogen-Activated Protein Kinases; Oropharyngeal Neoplasms; Oxidative Stress; Vasoactive Intestinal Peptide

A variety of tumor cells have been shown to express lipoprotein receptors. Recent data suggest that lipoprotein receptors may play a regulatory role in the growth of certain tumor cells. We investigated the effects of vasoactive intestinal peptide (VIP) and somatostatin-14 (SST-14) on the binding of 111Indium-labeled lipoproteins [(111)In-low density lipoprotein ((111)In-LDL), (111)In-high density lipoprotein ((111)In-HDL) and (111)In-very low density lipoprotein ((111)In-VLDL)] onto the epidermoid mammary carcinoma cell line A431. Scatchard analyses of the binding data indicated one class of specific high affinity binding sites for LDL, HDL and VLDL expressed by A431 cells, respectively. VIP increased significantly the binding capacity for (111)In-LDL on A431 cells. The VIP-induced increase of (111)In-LDL binding sites was inhibited by SST-14. Furthermore, SST-14 inhibited VIP-induced 3H-thymidine incorporation and adenosine 3'-5' cyclic monophosphate (cAMP) formation in A431 cells with IC50 values in the range of 5-7 nM. However, SST-14 showed no effect on dibutyryl-cAMP-induced increase of (111)In-LDL binding sites expressed on A431 cells. In contrast to (111)In-LDL binding, no effects of VIP or SST-14 on HDL or VLDL binding to A431 tumor cells were found. Our results suggest a direct effect of VIP and SST-14 on LDL-binding onto tumor cells. The complex interactions between VIP and SST-14 on LDL receptor expression of tumor cells may play a role in tumor cell lipid metabolism.

Topics: Bucladesine; Carcinoma, Squamous Cell; Cyclic AMP; Indium Radioisotopes; Kinetics; Lipoproteins, HDL; Lipoproteins, LDL; Lipoproteins, VLDL; Mammary Neoplasms, Animal; Receptors, Lipoprotein; Somatostatin; Temperature; Tumor Cells, Cultured; Vasoactive Intestinal Peptide

To identify the VIP biosynthetic pathways, we have isolated the human VIP gene, using synthetic oligodeoxynucleotides. These specific hybridization probes were constructed according to the neuroblastoma VIP-cDNA sequence and contained up to 39 bases. The gene structure was deduced by direct chemical nucleotide sequencing. Six exons were thus far discovered; among them two short exons, one encoding VIP and the second encoding PHM-27 (a peptide having a N-terminal histidine and C-terminal methionine amide, closely related in sequence and activity to VIP). As a model system for VIP gene expression, we used a human buccal tumor producing elevated amounts of VIP. In these cells, a major transcript of the VIP-gene was identified as a long RNA containing intron sequences. The occurrence of elevated quantities of a high molecular weight, intron containing, gene transcript which is not processed directly into mature RNA suggests that VIP gene expression may be regulated at the RNA processing level.

Topics: Base Sequence; Carcinoma, Squamous Cell; Gene Expression Regulation; Genes; Humans; RNA Processing, Post-Transcriptional; RNA, Neoplasm; Transcription, Genetic; Vasoactive Intestinal Peptide

The watery diarrhea-hypokalemia-achlorhydria syndrome associated with ectopic secretion of vasoactive intestinal peptide has only been conclusively documented with tumors originating in the pancreas or sympathetic chain. We report here the case of a 50-yr-old woman who developed this syndrome 3 wk after an apparently effective course of radiotherapy for an obstructing, mixed-cell carcinoma of the esophagus. High concentrations of vasoactive intestinal peptide were found in plasma (100-200 pmol/L; normal less than 20 pmol/L) and in the metastatic skin nodules (750 pmol/g) that later developed and that contained one of the two cell types from the original tumor. Stool volumes reached a plateau of 15-20 L/day, and potassium requirements were greater than 1000 mmol/day. Symptoms failed to respond to any of the regimens previously described as effective in this syndrome. After 14 wk of massive fecal fluid and electrolyte losses, symptoms resolved dramatically with the first dose of 5-fluorouracil. Plasma vasoactive intestinal peptide concentration returned to normal, where it remained despite subsequent evidence of renewed tumor spread. This case illustrates the unpredictability of the response of this syndrome to medical treatment, and suggests that vasoactive intestinal peptide secretion may occur in a wider range of tumors than has so far been described.

Topics: Achlorhydria; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Chromatography, High Pressure Liquid; Diarrhea; Esophageal Neoplasms; Female; Fluorouracil; Humans; Hypokalemia; Middle Aged; Streptozocin; Syndrome; Vasoactive Intestinal Peptide

The levels of immunoreactive-polypeptide hormones were measured in tissue extracts of eight uterine cervical cancers by specific radioimmunoassays. In one case with argyrophil granules, high levels of somatostatin, pancreatic polypeptide, calcitonin, and vasoactive intestinal polypeptide (VIP) were found, ranging from 160 to 880 ng/g tissue. A second argyrophil cancer contained 310 ng/g tissue of somatostatin, and a third contained 1100 ng/g tissue of adrenocorticotropic hormone (ACTH) and 380 ng/g of beta-melanocyte-stimulating hormone (beta-MSH). In addition, of the five nonargyrophil cancers tested, four contained calcitonin, three had VIP, two had either somatostatin or glucagon, and one contained ACTH and beta-MSH; the measured levels of these hormones ranged from 1.4 to 2.3 ng/g tissue. Gel filtration on a Sephadex G-75 column showed that the immunoreactive-polypeptide hormones in the first case were chromatographically similar to the authentic or prehormones. These results indicate that ectopic production of multiple immunoreactive-polypeptide hormones is common not only in argyrophil cell carcinoma, but also in nonargyrophil cell carcinoma of the cervix.

Topics: Adrenocorticotropic Hormone; Calcitonin; Carcinoma, Squamous Cell; Chromatography, Gel; Female; Glucagon; Humans; Melanocyte-Stimulating Hormones; Middle Aged; Radioimmunoassay; Silver; Somatostatin; Staining and Labeling; Uterine Cervical Neoplasms; Vasoactive Intestinal Peptide

Topics: 1-Methyl-3-isobutylxanthine; Carcinoma, Squamous Cell; Cell Line; Cyclic AMP; Gastrointestinal Hormones; Humans; Isoproterenol; Lung Neoplasms; Neoplasms, Experimental; Prostaglandins E; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Receptors, Gastrointestinal Hormone; Receptors, Vasoactive Intestinal Peptide; Secretin; Temperature; Time Factors; Vasoactive Intestinal Peptide