Repurposing salmon calcitonin for Glioblastoma Treatment: Targeting YAP/TAZ via Hippo pathway activation
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE319121 | GEO | 2026/02/10
REPOSITORIES: GEO
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Project description:The hormone calcitonin (CT) is primarily known for its pharmacologic action as an inhibitor of bone resorption, yet CT-deficient mice display increased bone formation. These findings raised the question about the underlying cellular and molecular mechanism of CT action. Here we show that either ubiquitous or osteoclast-specific inactivation of the murine CT receptor (CTR) causes increased bone formation. CT negatively regulates the osteoclast expression of Spns2 gene, which encodes a transporter for the signaling lipid sphingosine 1-phosphate (S1P). CTR-deficient mice show increased S1P levels, and their skeletal phenotype is normalized by deletion of the S1P receptor S1P3. Finally, pharmacologic treatment with the non-selective S1P receptor agonist FTY720 causes increased bone formation in wildtype, but not in S1P3-deficient mice. This study redefines the role of CT in skeletal biology, confirms that S1P acts as an osteoanabolic molecule in vivo, and provides evidence for a pharmacologically exploitable crosstalk between osteoclasts and osteoblasts. Osteoclasts of wildtype and Calcr-/- C57Bl/6 mice were treated with Calcitonin and compared to the non-treated osteoclasts of wildtype or Calcr-/- mice, respectively.
2014-10-19 | E-GEOD-60761 | biostudies-arrayexpress
Project description:Amylin (AmyR) and calcitonin (CTR) receptor co-agonists are currently in Phase II/III clinical trials for obesity treatment. Amylin binds to a heterodimeric receptor composed of CTR and the receptor activity modifying proteins 1, 2 or 3 (RAMP1-3). We investigated the role of amylin 1 and 3 (AMY1R, AMY3R) receptors in modulating the pharmacological effects of the dual amylin–calcitonin receptor agonists, cagrilintide and salmon calcitonin (sCT), in RAMP1/3 knockout (KO) mice. Male wild-type (WT) and KO littermate mice were fed high-fat diet for 23 weeks prior to the 3-week treatment period with vehicle, 150 nmol/kg sCT or 3 nmol/kg cagrilintide (SC, SID). Body weight loss was observed in WT cagrilintide-treated mice (-3.4 +/- 0.51 g, P<0.005; n=8/group), whereas sCT rather increased it (0.60 +/- 0.38 g, P<0.01; n=8/group). The absence of RAMP1 and RAMP3 impeded cagrilintide’s potency but improved sCT’s efficacy on weight loss. Cagrilintide and sCT both decreased food intake during the first few days of treatment in WT mice only (Day 1: veh 2.7 +/- 0.2 g; cagri 1.2 +/- 0.1 g, P<0.0001; sCT 1.5 +/- 0.2 g, P<0.0021; n=7-8/group). Both peptides activated cFos signal in neurons of the dorsal vagal complex (DVC) and lateral parabrachial nucleus (LPBN) of WT mice while AP cFos signal was decreased in cagrilintide-treated RAMP1/3 KO mice by 57% compared to WT cagrilintide-injected mice (P<0.001, n=5-6/group). Differential gene expression was analyzed in the DVC, LPBN and mediobasal hypothalamic area (MBH) of WT and RAMP1/3 KO mice. After 3 weeks of treatment, neither sCT nor cagrilintide significantly altered gene expression in the DVC or LPBN in WT mice. However, mRNA bulk sequencing points to a role of RAMP1/3 in synaptic function and receptor trafficking. Altogether, these results demonstrate the dependency of cagrilintide on AMY1R and AMY3R to lower body weight.
2025-06-05 | GSE296488 | GEO
Project description:The hormone calcitonin (CT) is primarily known for its pharmacologic action as an inhibitor of bone resorption, yet CT-deficient mice display increased bone formation. These findings raised the question about the underlying cellular and molecular mechanism of CT action. Here we show that either ubiquitous or osteoclast-specific inactivation of the murine CT receptor (CTR) causes increased bone formation. CT negatively regulates the osteoclast expression of Spns2 gene, which encodes a transporter for the signaling lipid sphingosine 1-phosphate (S1P). CTR-deficient mice show increased S1P levels, and their skeletal phenotype is normalized by deletion of the S1P receptor S1P3. Finally, pharmacologic treatment with the non-selective S1P receptor agonist FTY720 causes increased bone formation in wildtype, but not in S1P3-deficient mice. This study redefines the role of CT in skeletal biology, confirms that S1P acts as an osteoanabolic molecule in vivo, and provides evidence for a pharmacologically exploitable crosstalk between osteoclasts and osteoblasts.
2014-10-19 | GSE60761 | GEO
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2016-03-22 | E-GEOD-77423 | biostudies-arrayexpress
Project description:Glioblastoma (GBM) is a highly aggressive brain tumor with poor prognosis and high recurrence rates. The complex immune microenvironment of GBM is highly infiltrated by tumor-associated microglia and macrophages (TAMs). TAMs are known to be heterogeneous in their functional and metabolic states and can transmit either pro-tumoral or anti-tumoral signals to glioma cells. Here, we performed bulk RNA-seq and single-cell RNA-seq on GBM patient samples, which revealed increased ATP synthase expression and oxidative phosphorylation (OXPHOS) activity in TAMs located in the tumor core relative to the tumor periphery. Both in vitro and in vivo models displayed similar trends of augmented TAM mitochondrial activity, along with elevated mitochondrial fission, glucose uptake, mitochondrial membrane potential, and extracellular ATP (eATP) production by TAMs in the presence of GBM cells. Tumor-secreted factors, including GM-CSF, induced the increase in TAM eATP production. Elevated eATP in the GBM microenvironment promoted glioma growth and invasion by activating the P2X purinoceptor 7 (P2X7R) on glioma cells. Inhibition of the eATP-P2X7R axis attenuated tumor cell viability in vitro and reduced tumor size and prolonged survival in glioma-bearing mouse models. Overall, this study revealed elevated TAM-derived eATP in GBM and provided the basis for targeting the eATP-P2X7R signaling axis as a therapeutic strategy in GBM.
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Project description:Background & Aims: Late-stage primary biliary cholangitis (PBC) is defined by bile duct loss, ductular reaction, peribiliary inflammation and fibrosis. Loss of anion exchanger 2 (AE2), the ‘bicarbonate umbrella’ and ductulo-canalicular junctions (DCJ) are hypothesized to promote PBC progression. The secretin (Sct)/secretin receptor (SR) axis controls cystic fibrosis transmembrane receptor (CFTR) activation and AE2 opening, and controls choleresis. We aimed to define the impact of Sct/SR signaling on biliary secretory processes and subsequent injury in late-stage PBC mouse model and human samples. Methods: Female and male wild-type (WT) and dominant-negative transforming growth factor beta receptor II (dnTGFβRII, late-stage PBC model) at 32 wks of age were treated with Sct for 1 wk or 8 wks. Pathways mediated by Sct were identified by RNA-seq in isolated cholangiocytes. Sct/SR/CFTR/AE2 expression and MUC1 levels were evaluated in human control and late-stage PBC. Results: Biliary Sct, SR, CFTR and AE2 expression is reduced in late-stage PBC mouse models and human samples. Sct treatment decreased bile duct loss, ductular reaction, inflammation and fibrosis in late-stage PBC models, as well as hepatic bile acid release and DCJ formation. RNA-seq identified that Sct promoted mature epithelial cell marker expression, specifically anterior grade 2 (Agr2, expressed only in cholangiocytes). Late-stage PBC models and human samples had reduced biliary MUC1, which was enhanced with Sct treatment. Conclusion: Loss of the Sct/SR pathway in late-stage PBC results in a faulty ‘bicarbonate umbrella’ and reduced Agr2 and mucin production. Sct restores cholangiocyte secretory processes and DCJ formation through enhanced mature cholangiocyte phenotypes and healthy bile duct growth. The Sct/SR axis may be a therapeutic target for late-stage PBC patients.
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Project description:Kamihira2000 - calcitonin fibrillation kinetics
This model studies the kinetics of human calcitonin fibrillation described as a two-step process. Empirical data is used to determine the parameter values. Results show that the first step in fibrillation is a slow homogenous reaction and the second step is a fast autocatalytic heterogenous reaction.
This model is described in the article:
Conformational transitions
and fibrillation mechanism of human calcitonin as studied by
high-resolution solid-state 13C NMR.
Kamihira M, Naito A, Tuzi S, Nosaka
AY, Saitô H.
Protein Sci. 2000 May; 9(5):
867-877
Abstract:
Conformational transitions of human calcitonin (hCT) during
fibril formation in the acidic and neutral conditions were
investigated by high-resolution solid-state 13C NMR
spectroscopy. In aqueous acetic acid solution (pH 3.3), a local
alpha-helical form is present around Gly10 whereas a random
coil form is dominant as viewed from Phe22, Ala26, and Ala31 in
the monomer form on the basis of the 13C chemical shifts. On
the other hand, a local beta-sheet form as viewed from Gly10
and Phe22, and both beta-sheet and random coil as viewed from
Ala26 and Ala31 were detected in the fibril at pH 3.3. The
results indicate that conformational transitions from
alpha-helix to beta-sheet, and from random coil to beta-sheet
forms occurred in the central and C-terminus regions,
respectively, during the fibril formation. The increased 13C
resonance intensities of fibrils after a certain delay time
suggests that the fibrillation can be explained by a two-step
reaction mechanism in which the first step is a homogeneous
association to form a nucleus, and the second step is an
autocatalytic heterogeneous fibrillation. In contrast to the
fibril at pH 3.3, the fibril at pH 7.5 formed a local
beta-sheet conformation at the central region and exhibited a
random coil at the C-terminus region. Not only a hydrophobic
interaction among the amphiphilic alpha-helices, but also an
electrostatic interaction between charged side chains can play
an important role for the fibril formation at pH 7.5 and 3.3
acting as electrostatically favorable and unfavorable
interactions, respectively. These results suggest that hCT
fibrils are formed by stacking antiparallel beta-sheets at pH
7.5 and a mixture of antiparallel and parallel beta-sheets at
pH 3.3.
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2024-09-02 | BIOMD0000000614 | BioModels
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