Abstract:
:Increasing evidence highlighted the role of cancer stem cells (CSCs) in the development of tumor resistance to therapy, particularly in glioblastoma (GBM). Therefore, the development of new therapies, specifically directed against GBM CSCs, constitutes an important research avenue. Considering the extended range of cancer-related pathways modulated by histone acetylation/deacetylation processes, we studied the anti-proliferative and pro-apoptotic efficacy of givinostat (GVS), a pan-histone deacetylase inhibitor, on cell cultures enriched in CSCs, isolated from nine human GBMs. We report that GVS induced a significant reduction of viability and self-renewal ability in all GBM CSC cultures; conversely, GVS exposure did not cause a significant cytotoxic activity toward differentiated GBM cells and normal mesenchymal human stem cells. Analyzing the cellular and molecular mechanisms involved, we demonstrated that GVS affected CSC viability through the activation of programmed cell death pathways. In particular, a marked stimulation of macroautophagy was observed after GVS treatment. To understand the functional link between GVS treatment and autophagy activation, different genetic and pharmacological interfering strategies were used. We show that the up-regulation of the autophagy process, obtained by deprivation of growth factors, induced a reduction of CSC sensitivity to GVS, while the pharmacological inhibition of the autophagy pathway and the silencing of the key autophagy gene ATG7, increased the cell death rate induced by GVS. Altogether these findings suggest that autophagy represents a pro-survival mechanism activated by GBM CSCs to counteract the efficacy of the anti-proliferative activity of GVS. In conclusion, we demonstrate that GVS is a novel pharmacological tool able to target GBM CSC viability and its efficacy can be enhanced by autophagy inhibitory strategies.
journal_name
Front Mol Neuroscijournal_title
Frontiers in molecular neuroscienceauthors
Angeletti F,Fossati G,Pattarozzi A,Würth R,Solari A,Daga A,Masiello I,Barbieri F,Florio T,Comincini Sdoi
10.3389/fnmol.2016.00107subject
Has Abstractpub_date
2016-10-27 00:00:00pages
107issn
1662-5099journal_volume
9pub_type
杂志文章abstract::The post-synaptic density protein 95 (PSD-95) plays a central role in excitatory synapse development and synaptic plasticity. Phosphorylation of the N-terminus of PSD-95 at threonine 19 (T19) and serine 25 (S25) decreases PSD-95 stability at synapses; however, a molecular mechanism linking PSD-95 phosphorylation to al...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2020.00010
更新日期:2020-03-13 00:00:00
abstract::In the past two decades, yeast models have delivered profound insights into basic mechanisms of protein misfolding and the dysfunction of key cellular pathways associated with amyotrophic lateral sclerosis (ALS). Expressing ALS-associated proteins, such as superoxide dismutase (SOD1), TAR DNA binding protein 43 (TDP-4...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章,评审
doi:10.3389/fnmol.2018.00394
更新日期:2018-10-30 00:00:00
abstract::Potassium chloride co-transporter 2 (KCC2), a major chloride transporter that maintains GABAA receptor inhibition in mature mammalian neurons, is down-regulated in the hippocampus during epileptogenesis. Impaired KCC2 function accelerates or facilitates seizure onset. Calpain, with two main subtypes of m- and μ-calpai...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2018.00287
更新日期:2018-08-21 00:00:00
abstract::Laminin-α2-related congenital muscular dystrophy (LAMA2-CMD) is a devastating neuromuscular disease caused by mutations in the LAMA2 gene. These mutations result in the complete absence or truncated expression of the laminin-α2 chain. The α2-chain is a major component of the laminin-211 and laminin-221 isoforms, the p...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2020.00001
更新日期:2020-02-11 00:00:00
abstract::The competitive ectodomain shedding of amyloid-β precursor protein (APP) by α-secretase and β-secretase, and the subsequent regulated intramembrane proteolysis by γ-secretase are the key processes in amyloid-β peptides (Aβ) generation. Previous studies indicate that secretases form binary complex and the interactions ...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2018.00431
更新日期:2018-11-27 00:00:00
abstract::Synaptic vesicle proteins 2 (SV2) were discovered in the early 80s, but the clear demonstration that SV2A is the target of efficacious anti-epileptic drugs from the racetam family stimulated efforts to improve understanding of its role in the brain. Many functions have been suggested for SV2 proteins including ions or...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章,评审
doi:10.3389/fnmol.2017.00148
更新日期:2017-05-22 00:00:00
abstract::Intracerebral hemorrhage (ICH) is a subtype of stroke with highest mortality and morbidity. We have previously demonstrated that dipotassium bisperoxo (picolinato) oxovanadate (V), (bpV[pic]) inhibits phosphatase and tensin homolog (PTEN) and activates extracellular signal-regulated kinase (ERK)1/2. In this study, we ...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2019.00281
更新日期:2019-12-05 00:00:00
abstract::Proteolytic processing of the Amyloid Precursor Protein (APP) produces beta-amyloid (Aβ) peptide fragments that accumulate in Alzheimer's Disease (AD), but APP may also regulate multiple aspects of neuronal development, albeit via mechanisms that are not well understood. APP is a member of a family of transmembrane gl...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2016.00130
更新日期:2016-11-25 00:00:00
abstract::The tetrameric capsaicin receptor transient receptor potential vanilloid 1 (TRPV1) in mammals has evolved the capability to integrate pain signal arising from harmful temperature and chemical irritants. The four repetitions of TRPV1 subunits result in an ion channel with excellent pain sensitivity, allowing this ionot...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2019.00302
更新日期:2020-01-09 00:00:00
abstract::Neuronal identity is generated by the cell-surface expression of clustered protocadherin (Pcdh) isoforms. In mice, 58 isoforms from three gene clusters, Pcdhα, Pcdhβ, and Pcdhγ, are differentially expressed in neurons. Since cis-heteromeric Pcdh oligomers on the cell surface interact homophilically with that in other ...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2017.00114
更新日期:2017-04-24 00:00:00
abstract::In the brain, metabolic supply and demand is directly coupled to neuronal activation. Methods for culturing primary rodent brain cells have come of age and are geared toward sophisticated modeling of human brain physiology and pathology. However, the impact of the culture microenvironment on neuronal function is rarel...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2017.00305
更新日期:2017-09-29 00:00:00
abstract::Transcription factors regulate multiple processes during brain development and in the adult brain, from brain patterning to differentiation and maturation of highly specialized neurons as well as establishing and maintaining the functional neuronal connectivity. The members of the zinc-finger transcription factor fami...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章,评审
doi:10.3389/fnmol.2020.00051
更新日期:2020-04-08 00:00:00
abstract::Atypical Parkinson syndromes (APSs) often have symptoms that overlap with those of Parkinson's disease (PD), especially early in the disease, making these disorders difficult to diagnose. Previous studies have demonstrated an association of oligomeric α-synuclein (α-Syn), a key element in the pathogenesis of PD, with ...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2019.00129
更新日期:2019-06-12 00:00:00
abstract::The central, lateral and basolateral amygdala (BLA) nuclei are essential for the formation of long-term memories including emotional and drug-related memories. Studying cellular and molecular mechanisms of memory in amygdala may lead to better understanding of how memory is formed and of fear and addiction-related dis...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章,评审
doi:10.3389/fnmol.2016.00023
更新日期:2016-03-31 00:00:00
abstract::The tyrosine kinase Fyn plays an important role in synaptic plasticity, learning, and memory. Here we report that Fyn is activated in response to 15 min D1 receptor (D1R) but not D2 receptor (D2R) stimulation specifically in the dorsomedial striatum (DMS) of mice but not in the other substriatal regions, the dorsolate...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2017.00273
更新日期:2017-08-31 00:00:00
abstract::Convulsive seizures promote adult hippocampal neurogenesis (AHN) through a transient activation of neural stem/progenitor cells (NSPCs) in the subgranular zone (SGZ) of the dentate gyrus (DG). However, in a significant population of epilepsy patients, non-convulsive seizures (ncSZ) are observed. The response of NSPCs ...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2019.00031
更新日期:2019-02-19 00:00:00
abstract::In this review we provide an overview of key in vivo experiments undertaken in the cat spinal cord in the 1950s and 1960s, and point out their contributions to our present understanding of glycine receptor (GlyR) function. Importantly, some of these discoveries were made well before an inhibitory receptor, or its agon...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2010.00013
更新日期:2010-05-21 00:00:00
abstract::Alzheimer's disease (AD) is the most common cause of dementia and is characterized by the buildup of β-amyloid plaques and neurofibrillary Tau tangles. This leads to decreased synaptic efficacy, cell death, and, consequently, brain atrophy in patients. Behaviorally, this manifests as memory loss and confusion. Using a...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2020.594319
更新日期:2020-11-16 00:00:00
abstract::Microglial activation and the inflammatory response in the central nervous system (CNS) play important roles in secondary damage after traumatic brain injury (TBI). Transcriptional activation of genes that limit secondary damage to the CNS are mediated by a cis-acting element called the antioxidant responsive element ...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2018.00117
更新日期:2018-04-17 00:00:00
abstract::Peroxisome proliferator activated receptors (PPARs) are nuclear hormone receptors that act as transcription factors in response to endogenous lipid messengers. The fibrates and thiazolidinediones are synthetic PPAR agonists used clinically to treat dyslipidemia and Type 2 Diabetes Mellitus, respectively, but also impr...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2018.00331
更新日期:2018-09-19 00:00:00
abstract::Alzheimer's disease (AD) is a progressive disease with early degeneration of the central cholinergic neurons. Currently, three of four AD drugs act by inhibiting the acetylcholine (ACh) degrading enzyme, acetylcholinesterase (AChE). Efficacy of these drugs depends on available amount of ACh, which is biosynthesized by...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2019.00239
更新日期:2019-10-11 00:00:00
abstract::[This corrects the article on p. 257 in vol. 10, PMID: 28855859.]. ...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章,已发布勘误
doi:10.3389/fnmol.2017.00392
更新日期:2017-11-20 00:00:00
abstract::GABA(A) receptors are located on the majority of neurons in the central and peripheral nervous system, where they mediate important actions of the neurotransmitter gamma-aminobutyric acid. Early in development the trophic properties of GABA allow a healthy development of the nervous system. Most neurons have a high in...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/neuro.02.007.2008
更新日期:2008-05-30 00:00:00
abstract::In the brain, de novo gene expression driven by learning-associated neuronal activities is critical for the formation of long-term memories. However, the signaling machinery mediating neuronal activity-induced gene expression, especially the rapid transcription of immediate-early genes (IEGs) remains unclear. Cyclin-d...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2017.00365
更新日期:2017-11-07 00:00:00
abstract::GABAergic inhibitory neurotransmission contributes to diverse aspects of brain development and adult plasticity, including the expression of complex cognitive processes. This is afforded for in part by the dynamic adaptations occurring at inhibitory synapses, which show great heterogeneity both in terms of upstream si...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2019.00187
更新日期:2019-08-13 00:00:00
abstract::Stroke results in high morbidity and high mortality worldwide, with ischemic stroke accounting for 80% to 85%. As effective treatments for ischemic stroke remain limited because of the narrow therapeutic time window, a better understanding of the pathologic mechanism and new therapeutic intervention targets are needed...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章,评审
doi:10.3389/fnmol.2019.00061
更新日期:2019-03-22 00:00:00
abstract::Eukaryotic cells release different types of extracellular vesicles (EVs) including exosomes, ectosomes, and microvesicles. Exosomes are nanovesicles, 30-200 nm in diameter, that carry cell- and cell-state-specific cargo of proteins, lipids, and nucleic acids, including mRNA and miRNA. Recent studies have shown that ce...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章,评审
doi:10.3389/fnmol.2020.00038
更新日期:2020-03-19 00:00:00
abstract::Corticotropin releasing factor (CRF) has been shown to induce various behavioral changes related to adaptation to stress. Dysregulation of the CRF system at any point can lead to a variety of psychiatric disorders, including substance use disorders (SUDs). CRF has been associated with stress-induced drug reinforcement...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2012.00091
更新日期:2012-09-06 00:00:00
abstract::Immune checkpoints restrain the immune system following its activation and their inhibition unleashes anti-tumor immune responses. Immune checkpoint inhibitors revolutionized the treatment of several cancer types, including melanoma, and immune checkpoint blockade with anti-PD-1 and anti-CTLA-4 antibodies is becoming ...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章,评审
doi:10.3389/fnmol.2019.00282
更新日期:2019-11-21 00:00:00
abstract::The term neurodevelopmental disorder (NDD) is an umbrella term used to group together a heterogeneous class of disorders characterized by disruption in cognition, emotion, and behavior, early in the developmental timescale. These disorders are heterogeneous, yet they share common behavioral symptomatology as well as o...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章,评审
doi:10.3389/fnmol.2018.00132
更新日期:2018-04-24 00:00:00