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The Anti-Aging and Tumor Suppressor Protein Klotho Affects Signaling Pathwaysin a Human Oligodendroglioma Cell Line

ABSTRACT: Klotho functions as an aging suppressor, which, in mice, extends lifespan when overexpressed and accelerates development of aging-like phenotypes when disrupted. Klotho is mainly expressed in brain and kidney and is secreted into the serum and CSF. We have previously shown that Klotho is reduced in brains of old monkeys, rats and mice. We further reported the ability of Klotho to enhance oligodendrocyte differentiation and myelination. Here we examined the effects of Klotho on MO3.13, a human oligodendroglioma cell line in order to determine the potential role of Klotho as a tumor suppressor. We show that exogenous Klotho affects the ERK and Akt signaling pathways and decreases the proliferative abilities of MO3.13 cells. Furthermore, microarray analysis of Klotho-treated MO3.13 cells reveals a massive change in gene expression with 80% of the differentially expressed genes being downregulated. Using gene set enrichment analysis we predicted potential transcription factors involved in regulating Klotho-treated MO3.13 cells and found that these cells are highly enriched in the gene sets, that are similarly observed in cancer, cardiovascular disease, stress, aging and hormone-related chemical and genetic perturbations. Since Klotho is downregulated in all brain tumors tested to date, enhancing Klotho has therapeutic potential for treating brain malignancies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE51536 | GEO | 2014/06/09

SECONDARY ACCESSION(S): PRJNA223390

REPOSITORIES: GEO

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The Anti-Aging and Tumor Suppressor Protein Klotho Affects Signaling Pathwaysin a Human Oligodendroglioma Cell Line

Project description:Klotho functions as an aging suppressor, which, in mice, extends lifespan when overexpressed and accelerates development of aging-like phenotypes when disrupted. Klotho is mainly expressed in brain and kidney and is secreted into the serum and CSF. We have previously shown that Klotho is reduced in brains of old monkeys, rats and mice. We further reported the ability of Klotho to enhance oligodendrocyte differentiation and myelination. Here we examined the effects of Klotho on MO3.13, a human oligodendroglioma cell line in order to determine the potential role of Klotho as a tumor suppressor. We show that exogenous Klotho affects the ERK and Akt signaling pathways and decreases the proliferative abilities of MO3.13 cells. Furthermore, microarray analysis of Klotho-treated MO3.13 cells reveals a massive change in gene expression with 80% of the differentially expressed genes being downregulated. Using gene set enrichment analysis we predicted potential transcription factors involved in regulating Klotho-treated MO3.13 cells and found that these cells are highly enriched in the gene sets, that are similarly observed in cancer, cardiovascular disease, stress, aging and hormone-related chemical and genetic perturbations. Since Klotho is downregulated in all brain tumors tested to date, enhancing Klotho has therapeutic potential for treating brain malignancies. 6 Samples

2014-06-09 | E-GEOD-51536 | biostudies-arrayexpress

Activity-dependent neuronal Klotho enhances astrocytic aerobic glycolysis

Project description:Mutations of the β-glucuronidase protein α-Klotho have been associated with premature aging, and altered cognitive function. Although highly expressed in specific areas of the brain, Klotho functions in the central nervous system remain unknow. Here, we show that cultured hippocampal neurons respond to insulin and glutamate stimulation by elevating Klotho protein levels. Conversely, AMPA and NMDA antagonism suppress neuronal Klotho expression. We also provide evidence that soluble Klotho enhances astrocytic aerobic glycolysis by hindering pyruvate metabolism through the mitochondria, and stimulating its processing by lactate dehydrogenase. Pharmacological inhibition of FGFR1, Erk phosphorylation, and monocarboxylic acid transporters prevents Klotho-induced lactate release from astrocytes. Taken together these data suggest Klotho is a potential new player in the metabolic coupling between neurons and astrocytes. Neuronal glutamatergic activity and insulin modulation elicit Klotho release, which in turn stimulates astrocytic lactate formation and release. Lactate can then be used by neurons as a metabolic substrate contributing to fulfill their elevated energy requirements.

2018-03-08 | GSE100046 | GEO

Klotho suppresses colorectal cancer through modulation of the unfolded protein response

Project description:Study the role of klotho as a tumor suppressor in colorectal cancer. [abstract] Klotho is an anti-aging transmembrane protein, which can be shed and function as a hormone. Accumulating data indicate klotho as a tumor suppressor in a wide array of malignancies and indicate the subdomain KL1 as the active region of the protein. We aimed to study the role of klotho as a tumor suppressor in colorectal cancer. Bioinformatics analyses of TCGA datasets indicated reduced klotho mRNA levels in human colorectal cancer, along with negative regulation of klotho expression by hypermethylation of the promoter and 1st exon, and hypomethylation of an area within the gene. Overexpression or treatment with klotho or KL1 inhibited proliferation of colorectal cancer cells in vitro. The in vivo activity of klotho and KL1 was examined using two models recapitulating development of tumors in the normal colonic environment of immune-competent mice. Treatment with klotho inhibited formation of colon polyps induced by the carcinogen azoxymethane, and KL1 treatment slowed growth of orthotopically-implanted colorectal tumors. Gene expression array revealed that klotho and KL1 expression enhanced the unfolded protein response (UPR) and this was further established by increased levels of spliced XBP1, GRP78 and phosphorylated eIF2α. Furthermore, attenuation of the UPR partially abrogated klotho tumor suppressor activity. In conclusion, this study indicates klotho as a tumor suppressor in colorectal cancer and identifies, for the first time, the UPR as a pathway mediating klotho activities in cancer. These data suggest that administration of exogenous klotho or KL1 may serve as a novel strategy for prevention and treatment of colorectal cancer.

2018-08-09 | GSE118278 | GEO

MicorRNA expression in klotho-deficient and wild-type mouse brain subregions

Project description:The expression profiles of miRNAs in klotho-deficient and wild-type mouse brain subregions were examined. The data indicated that little or no marked difference in the miRNA expression was detected between them. Twelve samples prevared from 4- or 5-week-old klotho-deficient and wild-type mouse brain tissues (cerebrum, cerebellum and hippocampus) were examined.

2011-06-08 | E-GEOD-29092 | biostudies-arrayexpress

Platelet factor 4 (PF4) is induced by klotho and rejuvenates cognition and its molecular signature in the aging hippocampus

Project description:Platelet factors regulate wound healing and also signal from the blood to the brain. However, whether platelet factors modulate cognition, a highly valued and central manifestation of brain function, is unknown. Here, we show that systemic platelet factor 4 (PF4) modulates cognition and its molecular signature. Klotho, a longevity and cognition-enhancing protein, acutely activated platelets and increased circulating platelet factors, most robustly platelet factor 4 (PF4). To directly test PF4 effects on the brain, we treated mice with vehicle or systemic PF4. In young mice, PF4 enhanced synaptic plasticity and cognition. In aging mice, PF4 restored cognitive deficits and rejuvenated a molecular signature of cognition in the aging hippocampus. Augmenting platelet factors such as PF4, a possible messenger of klotho, may enhance cognition in the young brain and rejuvenate cognitive deficits in the aging brain.

2023-06-24 | GSE171929 | GEO

The biphasic and age-dependent impact of Klotho on hallmarks of aging and skeletal muscle function

Project description:Aging is accompanied by a disrupted information flow, which results from accumulation of molecular mistakes. These mistakes ultimately give rise to debilitating disorders such as skeletal muscle wasting, or sarcopenia. To estimate the growing “disorderliness” of the aging muscle system, we employed a statistical physics approach to estimate the state parameter, entropy, as a function of genes associated with hallmarks of aging. Although the most prominent structural and functional alterations were observed in the oldest old mice (27-29 months), we found that the escalating network entropy reached an inflection point at old age (22-24 months). To probe the potential for restoration of molecular “order” and reversal of the sarcopenic phenotype, we overexpressed the longevity protein, a-Klotho. Klotho overexpression modulated genes representing all hallmarks of aging in both old and oldest-old mice. However, whereas Klotho improved strength in old mice, intervention failed to induce a benefit beyond the entropic tipping point.

2021-04-01 | GSE156343 | GEO

Klotho inhibits neuronal senescence in human brain organoids

Project description:We report the application of brain organoids to study cellular senescence, in particular Klotho declining in expresssion mediates neuronal senescence, bulk RNA-sequencing further identified the potenital downstream target tha may modulate cellular senescence in the brain.

2021-04-09 | GSE171719 | GEO

Extrarenal α-klotho expression in human tissues

Project description:α-Klotho has emerged as a powerful regulator of the ageing process. To-date, the expression profile of α-Klotho in human tissues is unknown and its existence in some human tissue types is subject to much controversy. Objective: This is the first study to characterize system-wide tissue expression of transmembrane α-Klotho in humans. We have employed next generation targeted proteomic analysis using Parallel Reaction Monitoring (PRM) in parallel with conventional antibody-based methods to determine the expression and spatial distribution of human α-Klotho expression in health. Results: The distribution of α-Klotho in human tissues from various organ systems, including arterial, epithelial, endocrine, reproductive and neuronal tissues was first identified by immunohistochemistry. Kidney tissues showed strong α-Klotho expression, while liver did not reveal a detectable signal. These results were next confirmed by western blotting of both whole tissues and primary cells. To validate our antibody-based results, α-Klotho expressing tissues were subjected to PRM mass spectrometry identifying peptides specific for the full length, transmembrane α-Klotho isoform. Conclusions: The data presented confirms α-Klotho expression in the kidney tubule and in artery, and provides evidence of α-Klotho expression across organ systems and cell-types that have not previously been described in humans.

2015-10-13 | PXD002775 | Pride

Homo sapiens

Project description:The Anti-Aging and Tumor Suppressor Protein Klotho Affects Signaling Pathwaysin a Human Oligodendroglioma Cell Line

| PRJNA223390 | ENA

Histone Modification Analysis of Oligodendroglioma and Astrocytoma Brain Cancer Samples

Project description:WHO classification for tumors of the central nervous system strongly endorses molecular tests for the precise diagnosis of diffuse gliomas. While alterations in the DNA methylation status of gliomas are already well documented and used in specialised clinical centers to distinguish between brain tumor entities, changes to the epigenetic layer at the level of histone modifications are only poorly characterised. Here, we applied a recently developed data-independent acquisition (DIA) - mass spectrometry method to generate a comprehensive histone epi-proteomic map that documents the abundance of almost all characterized and many uncharacterized histone modifications to a series of IDH-mutant oligodendroglioma and astrocytoma samples. Our analysis documented significant abundance differences in almost one-third of the 144 quantified histone peptides. Among them are lower abundance levels of the polycomb repressive mark H3K27me3 in oligodendroglioma samples compared to astrocytomas. We validated this finding by immunohistochemistry using the C36B11 antibody. Surprisingly, we observed inconsistencies with another widely applied H3K27me3 antibody (07-449), providing a warning flag for immunohistochemistry of brain cancers. An unbiased unsupervised clustering analysis of the proteomic dataset separated the two IDH-mutant glioma subtypes in full accordance to the EPIC DNA methylation classifier and the 1p/19q status. The clustering also revealed at least two histone epi-proteomic subgroups of oligodendroglioma, a feature not observable in the DNA methylation dataset. Our results indicate that histone epi-proteomic profiling at the depth of the current method has the capacity to identify clinically-relevant glioma sub-groups. In addition to being of use for diagnostic purposes, this could also provide novel insights in glioma biology and may identify new therapeutic targets.

2020-01-17 | PXD015151 | Pride

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