TY - JOUR AB - BACKGROUND: Somatostatin analogs (SSAs) binding to and activating somatostatin receptors (SSTRs) have been extensively used for the treatment of neuroendocrine tumors (NETs). The currently approved synthetic SSAs have high affinity for SSTR2 (octreotide/lanreotide), or for SSTR2 and SSTR5 (pasireotide). These agents have shown symptoms control and antiproliferative effects in subsets of NET patients and this was associated to the expression of the targeted SSTRs. Pancreatic NETs (Pan-NETs) are uncommon tumors with a propensity to metastasize. For unresectable advanced Pan-NETs expressing SSTRs, SSAs are the first-line medical therapy. Pan-NETs express mainly SSTR1, SSTR2 and SSTR3 and thus should respond to agonists targeting SSTR3. SUMMARY: We evaluated the efficacy of ITF2984, a novel multireceptor agonist with specificity for SSTR3, against Pan-NET cells representative of well differentiated, functioning tumors, and expressing high levels of SSTR3. The effect of ITF2984 on cell proliferation/viability, and on its ability to promote apoptosis and suppress hormone secretion was evaluated in 2D and 3D organotypic culture systems. Pasireotide was tested in parallel for comparative purposes. KEY MESSAGE: We found that ITF2984 is as effective as pasireotide at inhibiting both proliferation/viability and hormone secretion, as well as at inducing apoptosis of Pan-NET cells grown as both 2D monolayers and 3D spheroids. High-dose ITF2984 elicits structural alterations in Pan-NET 3D spheroids compatible with cell death more effectively than pasireotide. Altogether, ITF2984 may represent a useful alternative to pasireotide for the medical treatment of Pan-NETs and other tumors with elevated SSTR3 expression. AU - Bistika, M.* AU - Marangelo, A.* AU - Ascione, F.* AU - Valentini, N.* AU - Fedeli, F.* AU - Schrader, J.* AU - Modena, D.* AU - Steinkühler, C.* AU - Pellegata, N.S. C1 - 73088 C2 - 56811 CY - Allschwilerstrasse 10, Ch-4009 Basel, Switzerland TI - The novel SSTR3 full agonist ITF2984 shows antitumor properties against pancreatic neuroendocrine tumors (Pan-NETs). JO - Neuroendocrinology PB - Karger PY - 2024 SN - 0028-3835 ER - TY - JOUR AB - Background: In peripheral tissues, the lipid droplet (LD) organelle links lipid metabolism, inflammation, and insulin resistance. Little is known about the brain LDs. Objectives: We hypothesized that hypothalamic LDs would be altered in metabolic diseases. Methods: We used immunofluorescence labeling of the specific LD protein, PLIN2, as the approach to visualize and quantify LDs. Results: LDs were abundant in the hypothalamic third ventricle wall layer with similar heterogeneous distributions between control mice and humans. The LD content was enhanced by high-fat diet (HFD) in both wild-type and in low-density lipoprotein receptor deficient (Ldlr-/-HFD) mice. Strikingly, we observed a lower LD amount in type 2 diabetes mellitus (T2DM) patients when compared with non-T2DM patients. Conclusions: LDs accumulate in the normal hypothalamus, with similar distributions in human and mouse. Moreover, metabolic diseases differently modify LD content in mouse and human. Our results suggest that hypothalamic LD accumulation is an important target to the study of metabolism. AU - Maya-Monteiro, C.M.* AU - Corrêa-da-Silva, F.* AU - Hofmann, S.M. AU - Hesselink, M.K.C.* AU - la Fleur, S.E.* AU - Yi, C.X.* C1 - 61426 C2 - 50241 CY - Allschwilerstrasse 10, Ch-4009 Basel, Switzerland SP - 263-272 TI - Lipid droplets accumulate in the hypothalamus of mice and humans with and without metabolic diseases. JO - Neuroendocrinology VL - 111 IS - 3 PB - Karger PY - 2021 SN - 0028-3835 ER - TY - JOUR AB - Background:Animal studies and initial correlative data in humans indicate that insulin action in the brain may affect pancreatic insulin secretion. An important brain region for this process is the hypothalamus, an area that can develop insulin resistance.Methods:Fifteen young, healthy men (27 +/- 3 years) with a wide BMI spectrum (20-30 kg/m(2)) underwent 2 hyperglycemic clamps (target blood glucose: 10 mmol/L). In this double-blind study, subjects received 160 U of insulin or placebo as a nasal spray on 2 days in randomized order. On another day, insulin sensitivity of the hypothalamus was determined by functional magnetic resonance imaging.Results:Glucose levels were comparable on both study days. In the whole group, C-peptide levels were not significantly different between conditions. Though, there was a significant interaction between insulin sensitivity of the hypothalamus x nasal spray x time on C-peptide levels (p= 10(-6)). The group was therefore divided according to median hypothalamic insulin sensitivity. C-peptide concentrations were higher after intranasal insulin compared to placebo spray in the group with a strong hypothalamic insulin response (p< 0.0001, beta = 6.00 +/- 1.24) and lower in the brain insulin-resistant group (p= 0.005, beta = -2.68 +/- 0.95). Neither somatostatin nor glucagon kinetics was altered by the nasal spray.Conclusions:In participants with high hypothalamic insulin sensitivity, insulin action in the brain enhanced second-phase insulin secretion from pancreatic beta cells. This reaction could, for example, contribute to late postprandial glucose regulation by suppressing hepatic glucose production by portal venous insulin. AU - Heni, M. AU - Wagner, R. AU - Willmann, C. AU - Jaghutriz, B.A. AU - Vosseler, A. AU - Kübler, C. AU - Hund, V.* AU - Scheffler, K.* AU - Peter, A. AU - Häring, H.-U. AU - Preissl, H. AU - Kullmann, S. AU - Fritsche, A. C1 - 57810 C2 - 47907 CY - Allschwilerstrasse 10, Ch-4009 Basel, Switzerland SP - 929-937 TI - Insulin action in the hypothalamus increases second phase insulin secretion in humans. JO - Neuroendocrinology VL - 110 IS - 11-12 PB - Karger PY - 2020 SN - 0028-3835 ER - TY - JOUR AB - Introduction: Glycogen synthase kinase 3α/β (GSK3α/β) is a serine/threonine kinase that plays a critical role in cancer. Aims: In this study, we evaluated the effects of the specific GSK3α/β inhibitor AR-A014418 in vitro to gain novel insights into GSK3α/β signaling in neuroendocrine tumors (NETs). Materials and Methods: Human NET cell lines (BON1, QGP1, H727, and GOT1) were treated with different concentrations of AR-A014418 alone and in combination with lovastatin, everolimus, 5-fluorouracil (5-FU), and γ-irradiation. Results: AR-A014418 significantly dose-and time-dependently decreased cell viability in all 4 NET cell lines through inhibition of epithelial growth factor receptor and mTORC1/p70S6K signaling, as well as cyclin D3 downregulation and induction of pChk1. In all cell lines tested, FACS analysis showed an AR-A014418-induced increase in the sub-G1 phase, reflecting cell death. Apoptosis induction was observed in H727, GOT1 and QGP1 cells, but not in BON1 cells. Furthermore, significant antimigratory effects upon GSK3α/β inhibition were found and were associated with β-catenin downregulation in all cell lines tested. Compensatory upregulation of pAkt and pERK in response to GSK3α/β inhibition was prevented by combining AR-A014418 with the ERK and Akt inhibitor lovastatin. Accordingly, the lovastatin/AR-A014418 combination was synergistic in BON1 and QGP1 cells. Moreover, AR-A014418 displayed promising chemosensitizing effects on 5-FU in QGP1 and slight radiosensitizing properties in BON1 and QGP1 cells. Conclusion: Our data provide new insights into the role of GSK3α/β in NETs and suggest that GSK3α/β inhibition could be a novel therapeutic option in NETs, especially in combination with lovastatin or 5-FU, depending on tumor entity. AU - Prada, A.E.T.* AU - Weis, C.* AU - Orth, M. AU - Lauseker, M.* AU - Spoettl, G.* AU - Maurer, J.* AU - Grabowski, P.* AU - Grossman, A.B.* AU - Auernhammer, C.J.* AU - Noelting, S.* C1 - 53800 C2 - 45006 CY - 1200 New York Ave, Nw, Washington, Dc 20005 Usa SP - 335-351 TI - GSK3α/β: A novel therapeutic target for neuroendocrine tumors. JO - Neuroendocrinology VL - 106 IS - 4 PB - Amer Assoc Advancement Science PY - 2018 SN - 0028-3835 ER - TY - JOUR AU - Richter, A. AU - Lalli, E.* AU - Sass, S. AU - Pellegata, N.S. C1 - 49989 C2 - 41949 CY - Basel SP - 8-8 TI - The Role of p27 in Pheochromocytoma Development. JO - Neuroendocrinology VL - 103 PB - Karger PY - 2016 SN - 0028-3835 ER - TY - JOUR AB - Aim: There is accumulating evidence that food consumption is controlled by a wide range of brain circuits outside of the homeostatic system. Activation in these brain circuits may override the homeostatic system and also contribute to the enormous increase of obesity. However, little is known about the influence of hormonal signals on the brain's non-homeostatic system. Thus, selective insulin action in the brain was investigated by using intranasal application. Methods: We performed 'resting-state' functional magnetic resonance imaging in 17 healthy lean female subjects to assess intrinsic brain activity by fractional amplitude of low-frequency fluctuations (fALFF) before, 30 and 90 min after application of intranasal insulin. Results: Here, we showed that insulin modulates intrinsic brain activity in the hypothalamus and orbitofrontal cortex. Furthermore, we could show that the prefrontal and anterior cingulate cortex response to insulin is associated with body mass index. Conclusion: This demonstrates that hormonal signals as insulin may reduce food intake by modifying the reward and prefrontal circuitry of the human brain, thereby potentially decreasing the rewarding properties of food. Due to the alarming increase in obesity worldwide, it is of great importance to identify neural mechanisms of interaction between the homeostatic and non-homeostatic system to generate new targets for obesity therapy. AU - Kullmann, S. AU - Frank, S.* AU - Heni, M.* AU - Ketterer, C.* AU - Veit, R.* AU - Häring, H.-U. AU - Fritsche, A. AU - Preissl, H. C1 - 11143 C2 - 30517 SP - 176-182 TI - Intranasal insulin modulates intrinsic reward and prefrontal circuitry of the human brain in lean women. JO - Neuroendocrinology VL - 97 IS - 2 PB - Karger PY - 2013 SN - 0028-3835 ER - TY - JOUR AB - Multiple endocrine neoplasias (MEN) are autosomal dominant disorders characterized by the occurrence of tumors in at least two endocrine glands. Two types of MEN syndromes have long been known: MEN type 1 (MEN1) and MEN type 2 (MEN2), associated with a different spectrum of affected organs. MEN1 and MEN2 are caused by germline mutations in the MEN1 tumor suppressor gene and the RET proto-oncogene, respectively. Lately, a new type of MEN was identified (named MEN4) which is due to mutations in the CDKN1B gene, encoding for p27kip1 (p27), a cyclin-dependent kinase (Cdk) inhibitor that regulates the transition of cells from G1 to S phase. p27 is a non-canonical tumor suppressor since it is usually not somatically mutated in human cancers but it is often downregulated by post-translational mechanisms. The discovery of MEN4 has defined a new role for CDKN1B as a tumor susceptibility gene for multiple endocrine tumors. To date, six germline CDKN1B mutations have been found in patients with a MEN1-like phenotype but negative for MEN1 mutations. Due to the limited number of patients so far identified, the phenotypic features of MEN4 are not clearly defined. Here, we review the clinical and molecular characteristics of the MEN4 syndrome and summarize the main functions of p27 to better comprehend how their alteration can predispose to neuroendocrine tumors. AU - Marinoni, I. AU - Pellegata, N.S. C1 - 2161 C2 - 27711 CY - Basel SP - 19-28 TI - p27kip1: A new multiple endocrine neoplasia gene? JO - Neuroendocrinology VL - 93 IS - 1 PB - Karger PY - 2011 SN - 0028-3835 ER - TY - JOUR AB - While incretins are of great interest for the therapy of diabetes 2, the focus has recently been brought to the thyroid, since rodents treated with glucagon-like peptide-1 (GLP-1) analogs were found to occasionally develop medullary thyroid carcinomas. Incretin receptors for GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) were therefore measured in various rodent and human thyroid conditions. In vitroGLP-1 and GIP receptor autoradiography were performed in normal thyroids, C-cell hyperplasia and medullary thyroid carcinomas in rodents. Receptor incidence and density were assessed and compared with the receptor expression in human thyroids, medullary thyroid carcinomas, and TT cells. GLP-1 receptors are expressed in C cells of normal rat and mice thyroids. Their density is markedly increased in rat C-cell hyperplasia and medullary thyroid carcinomas, where their incidence amounts to 100%. GIP receptors are neither detected in normal rodent thyroids nor in C-cell hyperplasia, but are present in all rat medullary thyroid carcinomas. No GLP-1 or GIP receptors are detected in normal human thyroids. Whereas only 27% of all human medullary thyroid carcinomas express GLP-1 receptors, up to 89% express GIP receptors in a high density. TT cells lack GLP-1 receptors but express GIP receptors. GLP-1 receptors are frequently expressed in non-neoplastic and neoplastic C cells in rodents while they are rarely detected in human C-cell neoplasia, suggesting species differences. Conversely, GIP receptors appear to be massively overexpressed in neoplastic C cells in both species. The presence of incretin receptors in thyroid C cell lesions suggests that this organ should be monitored before and during incretin-based therapy of diabetes. AU - Waser, B.* AU - Beetschen, K.* AU - Pellegata, N.S. AU - Reubi, J.C.* C1 - 6721 C2 - 29151 SP - 291-301 TI - Incretin receptors in non-neoplastic and neoplastic thyroid C cells in rodents and humans: Relevance for incretin-based diabetes therapy. JO - Neuroendocrinology VL - 94 IS - 4 PB - Karger PY - 2011 SN - 0028-3835 ER -