Effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE17167 | GEO | 2010/07/17
SECONDARY ACCESSION(S): PRJNA119769
REPOSITORIES: GEO
Similar Datasets
Project description:Monoamine oxidase A (MAO-A), a mitochondrial enzyme that degrades monoamines including neurotransmitters, is highly expressed in basal cells of the normal human prostatic epithelium and in poorly differentiated (Gleason grades 4 and 5), aggressive prostate cancer (PCa). Clorgyline, an MAO-A inhibitor, induces secretory differentiation of normal prostate cells. We systematically assessed gene expression changes induced by clorgyline in E-CA cells using high-density oligonucleotide microarrays. Genes differentially expressed in treated and control cells were identified by Significance Analysis of Microarrays. Expression of genes of interest was validated by quantitative real-time polymerase chain reaction. time series design
2010-07-17 | E-GEOD-17167 | biostudies-arrayexpress
Project description:Diabetes leads to cardiomyopathy and heart failure, the leading cause of death for diabetic patients. Monoamine oxidase (MAO)-dependent reactive oxygen species (ROS) formation contributes to the development of diabetic cardiomyopathy by inducing mitochondrial and cardiomyocyte dysfunction. Yet, it is unclear whether, in addition to the direct effects exerted by MAO-dependent ROS on mitochondria, MAO activity is able to post-transcriptionally regulate cardiomyocyte function and survival in diabetes. To this aim, we performed gene and miRNA expression profiling in cardiac tissue from a mouse model of type 1 diabetes (T1D) with or without pharmacological MAO inhibition. We found that MAO-dependent ROS generation in T1D hearts leads to profound transcriptomic changes, affecting autophagy and pro-survival pathways activation. MAO activity in T1D hearts affected expression levels of miR-133a-3p, -193a-3p, and -27a-3p that target insulin-like growth factor receptor 1 (Igf1r), growth factor receptor bound protein 10 and inositol polyphosphate 4 phosphatase type 1A, respectively, all components of the Igf1r/PI3K/Akt signaling pathway. Indeed, Akt activation was significantly downregulated in T1D hearts, whereas MAO inhibition restored the activation of this pro-survival pathway. The present study provides an important link between MAO activity, transcriptomic changes, and activation of pro-survival signaling and autophagy in diabetic cardiomyopathy.
2022-09-20 | GSE210611 | GEO
Project description:Monoamine oxidases MAOA and MAOB catalyze important cellular functions such as the deamination of neurotransmitters. Correspondingly, MAO inhibitors are used for the treatment of severe neuropsychiatric disorders such as depression. A commonly prescribed drug against refractory depression is tranylcypromine, however, the side effects are poorly understood. In order to decipher putative off-targets, we synthesized two tranylcypromine probes equipped with either an alkyne moiety or an alkyne-diazirine minimal photocrosslinker for in situ proteome profiling. Surprisingly, LC-MS/MS analysis revealed low enrichment of MAOA and relatively promiscuous labeling of proteins. Photoprobe labeling paired with fluorescent imaging studies revealed lysosomal trapping which could be largely reverted by the addition of lysosomotropic drugs.
2020-10-20 | PXD018580 | Pride
Project description:Diabetes leads to cardiomyopathy and heart failure, the leading cause of death for diabetic patients. Monoamine oxidase (MAO)-dependent reactive oxygen species (ROS) formation contributes to the development of diabetic cardiomyopathy by inducing mitochondrial and cardiomyocyte dysfunction. Yet, it is unclear whether, in addition to the direct effects exerted by MAO-dependent ROS on mitochondria, MAO activity is able to post-transcriptionally regulate cardiomyocyte function and survival in diabetes. To this aim, we performed gene and miRNA expression profiling in cardiac tissue from a mouse model of type 1 diabetes (T1D) with or without pharmacological MAO inhibition. We found that MAO-dependent ROS generation in T1D hearts leads to profound transcriptomic changes, affecting autophagy and pro-survival pathways activation. MAO activity in T1D hearts affected expression levels of miR-133a-3p, -193a-3p, and -27a-3p that target insulin-like growth factor receptor 1 (Igf1r), growth factor receptor bound protein 10 and inositol polyphosphate 4 phosphatase type 1A, respectively, all components of the Igf1r/PI3K/Akt signaling pathway. Indeed, Akt activation was significantly downregulated in T1D hearts, whereas MAO inhibition restored the activation of this pro-survival pathway. The present study provides an important link between MAO activity, transcriptomic changes, and activation of pro-survival signaling and autophagy in diabetic cardiomyopathy.
2022-09-20 | GSE210036 | GEO
Project description:Background: Genetic defects of monoamine neurotransmitters are rare neurological diseases amenable to treatment with variable response. They are major causes of early parkinsonism and other spectrum of movement disorders including dopa-responsive dystonia. Objectives: To conduct proteomic studies in cerebrospinal fluid (CSF) samples of patients with monoamine defects to detect biomarkers involved in pathophysiology, clinical phenotypes, and treatment response. Methods: 90 patients from diverse centers of the “International Working Group on Neurotransmitter Related Disorders” were included in the. Clinical and molecular metadata were related to the protein abundances in the CSF. Results: Concentrations of four proteins were significantly altered, detected by Mass spectrometry and confirmed by immunoassays. First, decreased levels of Apolipoprotein D were found in severe cases of aromatic L-amino acid decarboxylase deficiency. Second, low levels of Apolipoprotein H were observed in patients with the severe phenotype of tyrosine hydroxylase deficiency (THD), whereas increased concentrations of oligodendrocyte myelin glycoprotein were found in the same subset of THD patients. Third, decreased levels of Collagen6A3 were observed in treated tetrahydrobiopterin deficiency patients. Conclusion: This study, the largest cohort of patients with monoamine defects studied so far, reports the proteomic characterization of CSF and identify four novel biomarkers that bring new insights into the consequences of early dopaminergic deprivation in the developing brain. They open new possibilities to understand their role in the pathophysiology of these disorders and they may serve as potential predictors of disease severity and therapies.
2020-11-16 | PXD021642 | Pride
Project description:<p>Beyond motor neuron degeneration, homozygous mutations in the survival motor neuron 1 (SMN1) gene cause multiorgan and metabolic defects in patients with spinal muscular atrophy (SMA). However, the precise biochemical features of these alterations and the age of onset in the brain and peripheral organs remain unclear. Using untargeted NMR-based metabolomics in SMA mice, we identify cerebral and hepatic abnormalities related to energy homeostasis pathways and amino acid metabolism, emerging already at postnatal day 3 (P3) in the liver. Through HPLC, we find that SMN deficiency induces a drop in cerebral norepinephrine levels in overt symptomatic SMA mice at P11, affecting the mRNA and protein expression of key genes regulating monoamine metabolism, including aromatic L-amino acid decarboxylase (AADC), dopamine beta-hydroxylase (DβH) and monoamine oxidase A (MAO-A). In support of the translational value of our preclinical observations, we also discovered that SMN upregulation increases cerebrospinal fluid norepinephrine concentration in Nusinersen-treated SMA1 patients. Our findings highlight a previously unrecognized harmful influence of low SMN levels on the expression of critical enzymes involved in monoamine metabolism, suggesting that SMN-inducing therapies may modulate catecholamine neurotransmission. These results may also be relevant for setting therapeutic approaches to counteract peripheral metabolic defects in SMA. </p>
2023-11-27 | MTBLS8784 | MetaboLights
Project description:Transcriptional analysis of the effect of monoamine oxidase B (MAOB) in human prostate stromal cells (PrSC)
| PRJNA778245 | ENA
Project description:Inhibition of mechanistic target of rapamycin (mTOR) constitutes the standard of care of lymphangioleiomyomatosis (LAM). However, this treatment does not eradicate diseased cells and some patients show progressive decline of lung function. This study provides preclinical evidence for beneficial therapeutic approaches in combination with rapamycin. LAM tumorigenesis is reduced in vivo (ELT3-V3 tumor xenografts) using approved drugs for other human diseases and targeting monoamine oxidase A (MAO-A; clorgyline) or MAO-B (rasagiline).
2019-10-01 | GSE129399 | GEO
Project description:Purpose: Monoamine oxidase A (MAOA) is a mitochondrial enzyme that degrades neurotransmitters including serotonin and norepinephrine. Its inhibitors are commonly used to treat neurologic conditions including depression. Recently, we and others identified high expression of MAOA in normal basal prostate epithelium and in high grade primary prostate cancer (PCa). Inhibition of MAOA with an irreversible inhibitor, clorgyline, induced differentiation in primary cultures of epithelial cells from normal tissues and high grade cancers. Furthermore, clorgyline treatment inhibited several oncogenic pathways in PCa cells, suggesting a clinical value of MAOA inhibitors as a pro-differentiation and anti-oncogenic therapy for high risk PCa. Here, we extended our studies to a model of advanced PCa, VCaP cells, which were derived from castration-resistant metastatic PCa and express a high level of MAOA. Methods: The growth of VCaP cells in the presence or absence of clorgyline was evaluated in vitro and in vivo. Gene expression changes in response to clorgyline were determined by microarray and validated by quantitative real-time PCR. Results: Treatment with clorgyline in vitro inhibited growth and altered the transcriptional pattern of VCaP cells in a manner consistent with the pro-differentiation and anti-oncogenic effects seen in treated primary PCa cells. Src, beta-catenin, and MAPK oncogenic pathways, implicated in androgen-independent growth and metastasis, were significantly downregulated. Clorgyline treatment of mice bearing VCaP xenografts slowed tumor growth and induced transcriptome changes similar to those noted in vitro. Conclusions: Our results support the possibility that anti-depressant drugs that target MAOA might find a new application in treating PCa. Compound Based Treatment: Clorgyline treament of VCaP cells compound_treatment_design
2010-10-25 | E-GEOD-19822 | biostudies-arrayexpress
Project description:Prostate cancer (PCa) remains a prevalent and deadly disease. The histology-based Gleason score (GS) of PCa tissue biopsy is the most accurate predictor of disease aggressiveness and an important measure to guide decision-making with respect to treatment strategies and patient management. However, inherent variability associated with PCa tumour sampling and the subjective determination of the GS are still key challenges precluding accurate diagnostication and prognostication. Thus, novel molecular signatures are urgently needed to distinguish between indolent and aggressive forms of PCa for better patient management and outcomes. Herein, we have used label-free LC-MS/MS-based proteomics to profile the proteome of 50 PCa tissues spanning five GS-based PCa grades (n = 10 per group) relative to five tissues from individuals with benign prostatic hyperplasia (BPH). Over 2,000 proteins were consistently identified albeit at different levels between and within the patient groups, revealing biological processes associated with specific grades. Excitingly, a panel of 11 prostate-derived proteins including IGKV3D-20, RNASET2, TACC2, ANXA7, LMOD1, PRCP, GYG1, NDUFV1, H1FX, APOBEC3C, CTSZ displayed the potential to accurately stratify patients displaying low and high GS. This is the first study to characterise the prostate tissue proteome signatures of the five PCa grades relative to BPH. We report a panel of proteins that accurately can distinguish low and high GS PCa tissues. These promising proteins can be further explored as candidate biomarkers for PCa aggressiveness.
2019-10-09 | PXD013837 | Pride