scholarly journals Leptin and Notch Signaling Cooperate in Sustaining Glioblastoma Multiforme Progression

Biomolecules ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 886
Author(s):  
Salvatore Panza ◽  
Umberto Russo ◽  
Francesca Giordano ◽  
Antonella Leggio ◽  
Ines Barone ◽  
...  
Keyword(s):  
Glioblastoma Multiforme ◽  
Notch Signaling ◽  
Dominant Negative ◽  
Biologically Active ◽  
Gamma Secretase ◽  
Leptin Receptors ◽  
Downstream Effectors ◽  
Enhanced Expression ◽  
Forming Efficiency ◽  
The Central Nervous System

Glioblastoma multiforme (GBM) is the most malignant form of glioma, which represents one of the commonly occurring tumors of the central nervous system. Despite the continuous development of new clinical therapies against this malignancy, it still remains a deadly disease with very poor prognosis. Here, we demonstrated the existence of a biologically active interaction between leptin and Notch signaling pathways that sustains GBM development and progression. We found that the expression of leptin and its receptors was significantly higher in human glioblastoma cells, U-87 MG and T98G, than in a normal human glial cell line, SVG p12, and that activation of leptin signaling induced growth and motility in GBM cells. Interestingly, flow cytometry and real-time RT-PCR assays revealed that GBM cells, grown as neurospheres, displayed stem cell-like properties (CD133+) along with an enhanced expression of leptin receptors. Leptin treatment significantly increased the neurosphere forming efficiency, self-renewal capacity, and mRNA expression levels of the stemness markers CD133, Nestin, SOX2, and GFAP. Mechanistically, we evidenced a leptin-mediated upregulation of Notch 1 receptor and the activation of its downstream effectors and target molecules. Leptin-induced effects on U-87 MG and T98G cells were abrogated by the selective leptin antagonist, the peptide LDFI (Leu-Asp-Phe-Ile), as well as by the specific Notch signaling inhibitor, GSI (Gamma Secretase Inhibitor) and in the presence of a dominant-negative of mastermind-like-1. Overall, these findings demonstrate, for the first time, a functional interaction between leptin and Notch signaling in GBM, highlighting leptin/Notch crosstalk as a potential novel therapeutic target for GBM treatment.

scholarly journals Peroxisome biogenesis deficiency attenuates the BDNF-TrkB pathway-mediated development of the cerebellum

2018 ◽  
Vol 1 (6) ◽  
pp. e201800062 ◽  
Author(s):  
Yuichi Abe ◽  
Masanori Honsho ◽  
Ryota Itoh ◽  
Ryoko Kawaguchi ◽  
Masashi Fujitani ◽  
...  
Keyword(s):  
Dominant Negative ◽  
Neurological Deficits ◽  
Peroxisome Biogenesis ◽  
Peroxisomal Biogenesis ◽  
Extracellular Signal ◽  
Enhanced Expression ◽  
Assembly Factor ◽  
Model Mouse ◽  
Cortical Laminar ◽  
The Central Nervous System

Peroxisome biogenesis disorders (PBDs) manifest as neurological deficits in the central nervous system, including neuronal migration defects and abnormal cerebellum development. However, the mechanisms underlying pathogenesis remain enigmatic. Here, to investigate how peroxisome deficiency causes neurological defects of PBDs, we established a new PBD model mouse defective in peroxisome assembly factor Pex14p, termed Pex14ΔC/ΔC mouse. Pex14ΔC/ΔC mouse manifests a severe symptom such as disorganization of cortical laminar structure and dies shortly after birth, although peroxisomal biogenesis and metabolism are partially defective. The Pex14ΔC/ΔC mouse also shows malformation of the cerebellum including the impaired dendritic development of Purkinje cells. Moreover, extracellular signal-regulated kinase and AKT signaling are attenuated in this mutant mouse by an elevated level of brain-derived neurotrophic factor (BDNF) together with the enhanced expression of TrkB-T1, a dominant-negative isoform of the BDNF receptor. Our results suggest that dysregulation of the BDNF-TrkB pathway, an essential signaling for cerebellar morphogenesis, gives rise to the pathogenesis of the cerebellum in PBDs.

scholarly journals Notch Signaling Regulation in HCC: From Hepatitis Virus to Non-Coding RNAs

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 521
Author(s):  
Catia Giovannini ◽  
Francesca Fornari ◽  
Fabio Piscaglia ◽  
Laura Gramantieri
Keyword(s):  
Notch Signaling ◽  
Cell Fate ◽  
Hepatitis Virus ◽  
Notch Pathway ◽  
Notch Receptor ◽  
Gamma Secretase ◽  
Stem Cell Maintenance ◽  
Pathway Activation ◽  
Promising Therapeutic Approach ◽  
Conserved Genes

The Notch family includes evolutionary conserved genes that encode for single-pass transmembrane receptors involved in stem cell maintenance, development and cell fate determination of many cell lineages. Upon activation by different ligands, and depending on the cell type, Notch signaling plays pleomorphic roles in hepatocellular carcinoma (HCC) affecting neoplastic growth, invasion capability and stem like properties. A specific knowledge of the deregulated expression of each Notch receptor and ligand, coupled with resultant phenotypic changes, is still lacking in HCC. Therefore, while interfering with Notch signaling might represent a promising therapeutic approach, the complexity of Notch/ligands interactions and the variable consequences of their modulations raises concerns when performed in undefined molecular background. The gamma-secretase inhibitors (GSIs), representing the most utilized approach for Notch inhibition in clinical trials, are characterized by important adverse effects due to the non-specific nature of GSIs themselves and to the lack of molecular criteria guiding patient selection. In this review, we briefly summarize the mechanisms involved in Notch pathway activation in HCC supporting the development of alternatives to the γ-secretase pan-inhibitor for HCC therapy.

Glioblastoma Multiforme with Hypodipsic Hypernatremia in a Seven-Month-Old Golden Retriever

2016 ◽  
Vol 52 (5) ◽  
pp. 319-324 ◽  
Author(s):  
Stephanie Engel ◽  
Karen Marie Hilling ◽  
Travis Kuder Meuten ◽  
Chad Brendan Frank ◽  
Angela J. Marolf
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Glioblastoma Multiforme ◽  
Glial Cell ◽  
Congenital Malformations ◽  
Cell Tumor ◽  
Golden Retriever ◽  
Neoplastic Process ◽  
Underlying Causes ◽  
The Central Nervous System

ABSTRACT Primary hypodipsic hypernatremia is a rarely reported disease in dogs. Reported underlying causes associated with this disease in dogs include congenital malformations, encephalitis, intracranial neoplasia, and pressure atrophy of the hypothalamus secondary to hydrocephalus. The dog in this report had an infiltrative neoplastic disorder, likely causing damage to the hypothalamic osmoreceptors responsible for the thirst generation. The neoplastic process was identified histopathologically as glioblastoma multiforme, an unusual tumor to occur in a dog this young. A tumor of the central nervous system causing physical destruction of the osmoreceptors has rarely been reported in dogs and none of the previously reported cases involved a glial cell tumor.

scholarly journals Glioblastoma Multiforme—A Look at the Past and a Glance at the Future

Pharmaceutics ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1053
Author(s):  
Jasmine L. King ◽  
Soumya Rahima Benhabbour
Keyword(s):  
Glioblastoma Multiforme ◽  
Immune Surveillance ◽  
Standard Of Care ◽  
Current Standard ◽  
Comprehensive Overview ◽  
Therapeutic Delivery ◽  
The Past ◽  
Adults And Children ◽  
The Central Nervous System ◽  
Delivery Strategies

Gliomas are the most common type of brain tumor that occur in adults and children. Glioblastoma multiforme (GBM) is the most common, aggressive form of brain cancer in adults and is universally fatal. The current standard-of-care options for GBM include surgical resection, radiotherapy, and concomitant and/or adjuvant chemotherapy. One of the major challenges that impedes success of chemotherapy is the presence of the blood–brain barrier (BBB). Because of the tightly regulated BBB, immune surveillance in the central nervous system (CNS) is poor, contributing to unregulated glioma cell growth. This review gives a comprehensive overview of the latest advances in treatment of GBM with emphasis on the significant advances in immunotherapy and novel therapeutic delivery strategies to enhance treatment for GBM.

Natural products targeting cancer stem cells: a revisit

2021 ◽  
Vol 28 ◽  
Author(s):  
Jiahua Cui ◽  
Jiajun Qian ◽  
Larry Ming-Cheung Chow ◽  
Jinping Jia
Keyword(s):  
Stem Cells ◽  
Drug Resistance ◽  
Natural Products ◽  
Cancer Stem Cells ◽  
Therapeutic Potential ◽  
Tumor Development ◽  
Biologically Active ◽  
Cellular Targets ◽  
Drug Candidates ◽  
Enhanced Expression

Background: The proposed central role of cancer stem cells (CSCs) in tumor development has been extended to explain the diverse oncologic phenomena such as multidrug resistance, metastasis and tumor recurrence in clinics. Due to the enhanced expression of ATP-binding cassette transporters and anti-apoptotic factors, stagnation on G0 phase and the strong ability of self-renewal, the CSCs were highly resistant to clinical anticancer drugs. Therefore, the discovery of new drug candidates that could effectively eradicate cancer stem cells afforded promising outcomes in cancer therapy. Introduction: Natural products and their synthetic analogues are a rich source of biologically active compounds and several of them have already been recognized as potent CSCs killers. We aim to provide a collection of recently identified natural products that suppressed the survival of the small invasive CSC populations and combated the drug resistance of these cells in chemotherapy. Results and Conclusion: These anti-CSCs natural products included flavonoids, stilbenes, quinones, terpenoids, polyketide antibiotics, steroids and alkaloids. In the present review, we highlighted the therapeutic potential of natural products and their derivatives against the proliferation and drug resistance of CSCs, their working mechanisms and related structure-activity relationships. Meanwhile, in this survey, several natural products with diverse cellular targets such as the naphthoquinone shikonin and the stilbene resveratrol were characterized as promising lead compounds for future development.

scholarly journals TAMI-11. IMPACT OF oHSV ACTIVATED NOTCH SIGNALING IN TUMOR MICROENVIRONMENT, AND ITS IMPACT ON ANTI-TUMOR IMMUNITY

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii215-ii215
Author(s):  
Yoshihiro Otani ◽  
Ji Young Yoo ◽  
Samantha Chao ◽  
Toshihiko Shimizu ◽  
Cole Lewis ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Notch Signaling ◽  
Tumor Immunity ◽  
Cell Communication ◽  
Notch Signaling Pathway ◽  
Therapeutic Benefit ◽  
Notch Receptor ◽  
Negative Regulator ◽  
Gamma Secretase ◽  
The Impact

Abstract NOTCH signaling is a method of cell-cell communication where membrane bound NOTCH ligands on signal-sending cells can bind to and initiate cleavage of the NOTCH receptor, releasing NICD which can initiate signal transduction in adjacent “signal-receiving” cells. We have recently shown that oHSV treatment of GBM cells induces NICD cleavage and NOTCH activation in adjacent uninfected glioma cells. RNA sequencing of GBM cells post-infection also uncovered Gene Ontology NOTCH signaling pathway to be significantly upregulated. This activation was induced by viral miRNA-H16, which represses FIH-1 expression. FIH-1 was found to be a negative regulator of Mib1, a ubiquitin ligase, which activates NOTCH ligand-mediated activation of adjacent signal-receiving cells bearing the NOTCH receptor (Otani et al Clin. Can. Res. 2020). Here we have investigated the impact of oHSV-induced NOTCH signaling on the tumor microenvironment. Treatment of brain tumors in immune competent mice with oHSV and NOTCH blocking gamma secretase inhibitor (GSI) induced an anti-tumor memory immune response. Long term survivors in mice treated with the combination also completely rejected subsequent tumor re-challenge in the other hemisphere. UMAP of flow cytometry of tumor-bearing hemispheres and functional analysis of isolated cellular fractions from treated mice showed a significant influx of MDSC cells after oHSV treatment that was rescued in mice treated with oHSV and GSI. Ongoing mechanistic studies are uncovering a significant induction of NOTCH in tumor associated macrophages that aids in recruitment of MDSC cells. Overall these studies have uncovered a significant impact of oHSV therapy on GBM tumor microenvironment and presents opportunities for combination therapies that can help improve therapeutic benefit and anti-tumor immunity.

scholarly journals mTORC1 is necessary but mTORC2 and GSK3β are inhibitory for AKT3-induced axon regeneration in the central nervous system

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Linqing Miao ◽  
Liu Yang ◽  
Haoliang Huang ◽  
Feisi Liang ◽  
Chen Ling ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Axon Regeneration ◽  
Nodal Point ◽  
Mtor Signaling ◽  
Negative Regulator ◽  
Molecular Dissection ◽  
Parallel Pathways ◽  
Downstream Effectors ◽  
The Central Nervous System

Injured mature CNS axons do not regenerate in mammals. Deletion of PTEN, the negative regulator of PI3K, induces CNS axon regeneration through the activation of PI3K-mTOR signaling. We have conducted an extensive molecular dissection of the cross-regulating mechanisms in axon regeneration that involve the downstream effectors of PI3K, AKT and the two mTOR complexes (mTORC1 and mTORC2). We found that the predominant AKT isoform in CNS, AKT3, induces much more robust axon regeneration than AKT1 and that activation of mTORC1 and inhibition of GSK3β are two critical parallel pathways for AKT-induced axon regeneration. Surprisingly, phosphorylation of T308 and S473 of AKT play opposite roles in GSK3β phosphorylation and inhibition, by which mTORC2 and pAKT-S473 negatively regulate axon regeneration. Thus, our study revealed a complex neuron-intrinsic balancing mechanism involving AKT as the nodal point of PI3K, mTORC1/2 and GSK3β that coordinates both positive and negative cues to regulate adult CNS axon regeneration.

scholarly journals Temporal effects of Notch signaling and potential cooperation with multiple downstream effectors on adenohypophysis cell specification in zebrafish

2016 ◽  
Vol 21 (5) ◽  
pp. 492-504 ◽  
Author(s):  
Yoshinari Nakahara ◽  
Akihiko Muto ◽  
Ryo Hirabayashi ◽  
Tetsushi Sakuma ◽  
Takashi Yamamoto ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Cell Specification ◽  
Temporal Effects ◽  
Downstream Effectors
Sign in / Sign up

Export Citation Format

Share Document