sincalide and Astrocytoma

Gliomas are highly malignant tumors, the most common of which are astrocytomas. A growing number of studies suggest that dysregulation of miRNAs is a frequent event contributing to the pathogenesis of gliomas. In this study, we found that over-expression of miR-132 inhibited cell proliferation and migration and triggered apoptosis, while knockdown of miR-132 showed opposite effects. PEA-15 was identified as a direct target of miR-132. Reintroduction of PEA-15 without 3'UTR region reversed the inhibitory effects of miR-132 on cell proliferation, migration, and apoptosis. MiR-132 was inversely correlated with the PEA-15 expression. CREB (cAMP response element binding protein) and KLF (Krüppel-like factor 8) were conformed as transcription factors of miR-132, which bidirectionally regulate the expression of miR-132. Our study suggests that miR-132 is an important tumor suppressor of astrocytoma progression by targeting PEA-15, while CREB and KLF can modulate the expression of miR-132, thus providing new insight into the molecular mechanisms underlying astrocytoma progression in vitro.

Topics: Analysis of Variance; Apoptosis; Apoptosis Regulatory Proteins; Astrocytoma; Brain Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; CREB-Binding Protein; Disease Progression; Gene Expression Regulation, Neoplastic; Glioma; HEK293 Cells; Humans; Intracellular Signaling Peptides and Proteins; Kruppel-Like Transcription Factors; MicroRNAs; Phosphoproteins; Repressor Proteins; RNA, Messenger; Sincalide; Time Factors; Transfection

Drosophila lethal (2) giant larvae (lgl) has been reported as a tumor suppressor and could regulate the Drosophila hippo signaling. Human giant larvae-1(Hugl-1), one human homologue of Drosophila lgl, also has been reported to be involved in the development of some human cancers. However, whether Hugl-1 is associated with the pathogenesis of malignant gliomas remains poorly understood. In the present work, we examined the effect of Hugl-1 on glioma cell growth both in vitro and in vivo. Firstly, we found that Hugl-1 protein levels decreased in the human glioma tissues, suggesting that Hugl-1 is involved in glioma progression. Unfortunately, either stably or transiently over-expressing Hugl-1 did not affect glioma cell proliferation in vitro. In addition, Hugl-1 over-expression did not regulate hippo signaling pathway. Interestingly, over-expression of Hugl-1 not only inhibited gliomagenesis but also markedly inhibited cell proliferation and promoted the apoptosis of U251 cells in an orthotopic model of nude mice. Taken together, this study provides the evidence that Hugl-1 inhibits glioma cell growth in intracranial model of nude mice, suggesting that Hugl-1 might be a potential tumor target for glioma therapy.

Topics: Animals; Astrocytoma; Brain Neoplasms; Cell Line, Tumor; Cell Proliferation; Cytoskeletal Proteins; Disease Models, Animal; Female; Gene Expression Regulation, Neoplastic; Green Fluorescent Proteins; Humans; Ki-67 Antigen; Male; Mice; Mice, Nude; Phenylurea Compounds; Sincalide; Transfection

Human astrocytic tumors grow into the normal brain parenchyma either as localized tumors, or as highly diffuse neoplasms. The diffuse phenotype relates to a specific sub-type of neoplastic astrocytes with a high motility and invasion capacity. Motility features refer to locomotion while invasion features refer to protease secretion. Our data reveal that several peptides belonging to the gastrin/cholecystokinin peptide class are able to significantly (and in certain cases very significantly) modify the level of tumor growth (at the level of cell proliferation and/or cell death), of motility and of invasion in various experimental models of human astrocytic tumors. We are synthesizing various gastrin/cholecystokinin-related peptides in order to develop clinical applications with which we want to inhibit astrocytic tumor growth, individual neoplastic astrocytic motility and the invasion of the normal brain parenchyma.

Topics: Animals; Astrocytoma; Biomarkers, Tumor; Brain Neoplasms; Disease Models, Animal; Drug Evaluation, Preclinical; Gastrins; Humans; Mice; Sincalide

Gastrin and cholecystokinin (CCK) mediate their effects through at least two types of receptors (CCK receptors A and B). While it has been hypothesized that gastrin, a stimulator of gastric acid secretion, is also a neurotransmitter and a stimulator of cell proliferation in various normal and neoplastic tissues, its effect on astrocytic brain tumors has not been actively investigated.. Our goal was to determine the effects of gastrin and gastin and/or CCK antagonists on the proliferation in vitro of astrocytic tumor cells by use of both established cell lines and primary cell cultures of tumor tissue.. Ten established astrocytic tumor cell lines, SW1088, SW1783, Hs683, H4, U87, U118, U138, U373, T98G, and A172, were studied. The effects of added gastrin (at 0.01, 0.1, and microM) and the gastrin/CCK antagonists L-365,260, CI-988, L-364,718, and JMV 234 (each at 0.01, 0.1, and 1 microM) on the cellular proliferation rates of the 10 cell lines were indirectly measured by use of the colorimetric tetrazolium assay. The influence of gastrin (at 0.01 microM) on the cellular proliferation of primary cultures from nine freshly explanted astrocytic tumors was assessed by means of tritiated thymidine uptake and autoradiography.. At specific concentrations, added gastrin increased the cellular proliferation of three established astrocytic cell lines (A172, Hs683, and SW1088), decreased it in two (U373 and T98G), and was without effect on the remaining five. Gastrin decreased cellular proliferation in one primary astrocytic tumor cell culture, stimulated it in five, and had no apparent effect in the remaining three. L-365,260, a CCK receptor B antagonist used at 0.01 microM, increased cellular proliferation in seven cell lines (A172, H4, Hs683, SW1783, T98G, U118, and U138), decreased it in one (U87), and had no effect in the remaining two. CI-988, another CCK receptor B antagonist used at 0.01 microM, inhibited cellular proliferation in five cell lines (A172, H4, SW1783, U373, and U87), stimulated it in two (T98G and U138), and had no effect in three. The CCK receptor A antagonists L-364,718 and JMV 234, both used at 0.01 microM, affected the cellular proliferation of only three of the 10 cell lines.. These results suggest that gastrin (and perhaps CCK that belongs to the same peptide family) may play a role in the growth of a substantial proportion of human astrocytic tumors.

Topics: Amino Acid Sequence; Astrocytoma; Autoradiography; Benzodiazepinones; Brain Neoplasms; Cell Division; Cholecystokinin; Devazepide; Gastrins; Hormone Antagonists; Humans; Indoles; Meglumine; Molecular Sequence Data; Peptide Fragments; Phenylurea Compounds; Receptors, Cholecystokinin; Sincalide; Thymidine; Tritium; Tumor Cells, Cultured

We have investigated the potential role of gastrin in the regulation of cell growth in human astrocytic tumors. To this end we have used synthetic analogs of gastrin and cholecystokinin (CCK) which behave as gastrin and/or CCK antagonists, e.g. compounds JMV-97, JMV-209 and JMV-179. Their effects on astrocytic tumor cell proliferation was investigated by the use of the colorimetric MTT assay. The in vitro biological models used in the present study included the SW1088, U87 and U373 astrocytic tumor cell lines. The results demonstrated marked influence of gastrin and CCK antagonists in the regulation of astrocytic tumor growth. This suggests that gastrin and/or CCK antagonists might be tested in experimental glioblastoma.

Topics: Astrocytes; Astrocytoma; Brain Neoplasms; Cholecystokinin; Gastrins; Glioblastoma; Humans; Peptide Fragments; Sincalide; Tumor Cells, Cultured

Topics: Astrocytoma; Cell Line; Cell Membrane; Cholecystokinin; Glycopeptides; Humans; Hydrolysis; Kinetics; Neprilysin; Neuroblastoma; Sincalide; Tumor Cells, Cultured