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Cytosolic Extract of Human Adipose Stem Cells Reverses the Amyloid Beta-Induced Mitochondrial Apoptosis via P53/Foxo3a Pathway.

ABSTRACT: Human adipose stem cells (hASC) have therapeutic potential for the treatment of neurodegenerative disorders. Mitochondrial dysfunction is frequently observed in most neurodegenerative disorders, including Alzheimer's disease. We explored the therapeutic potential of hASC cytosolic extracts to attenuate neuronal death induced by mitochondrial dysfunction in an Alzheimer's disease (AD) in vitro models. Amyloid beta (A?) was used to induce cytotoxity in an immortal hippocampal cell line (HT22) and neuronal stem cells from the brain of TG2576 transgenic mice were also used to test the protective role of hASC cytosolic extracts. Cell viability and flow cytometry results demonstrated that the hASC extract prevents the toxicity and apoptosis in AD in vitro models. Moreover, JC-1 and MitoSoxRed staining followed by fluorescence microscopy and flow cytometry results showed that the hASC extract ameliorated the effect of A?-induced mitochondrial oxidative stress and reduced the mitochondrial membrane potential. Western blot result showed that hASC extract modulated mitochondria-associated proteins, such as Bax and Bcl2, and down-regulated cleaved caspase-3. In addition, hASC extract decreased A? generation and reversed up-regulated p53 and foxo3a protein level in AD in vitro model cell derived from TG2576 mice. Taken together, these findings implicate a protective role of the hASC extract in the A?-induced mitochondrial apoptosis via regulation of P53/foxo3a pathway, providing insight into the molecular mechanisms of hASC extract and a therapeutic strategy to ameliorate neuronal death induced by A?.

SUBMITTER: Liu T

PROVIDER: S-EPMC5207391 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Cytosolic Extract of Human Adipose Stem Cells Reverses the Amyloid Beta-Induced Mitochondrial Apoptosis via P53/Foxo3a Pathway.

Liu Tian T Lee Mijung M Ban Jae-Jun JJ Im Wooseok W Mook-Jung Inhee I Kim Manho M

PloS one 20170103 1

Human adipose stem cells (hASC) have therapeutic potential for the treatment of neurodegenerative disorders. Mitochondrial dysfunction is frequently observed in most neurodegenerative disorders, including Alzheimer's disease. We explored the therapeutic potential of hASC cytosolic extracts to attenuate neuronal death induced by mitochondrial dysfunction in an Alzheimer's disease (AD) in vitro models. Amyloid beta (Aβ) was used to induce cytotoxity in an immortal hippocampal cell line (HT22) and ...[more]

PMID: 28046000

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Project description:BackgroundPlants have proved to be an important source of anti-cancer drugs. Here we have investigated the cytotoxic action of an aqueous extract of Fagonia cretica, used widely as a herbal tea-based treatment for breast cancer.Methodology/principal findingsUsing flow cytometric analysis of cells labeled with cyclin A, annexin V and propidium iodide, we describe a time and dose-dependent arrest of the cell cycle in G0/G1 phase of the cell cycle and apoptosis following extract treatment in MCF-7 (WT-p53) and MDA-MB-231 (mutant-p53) human breast cancer cell lines with a markedly reduced effect on primary human mammary epithelial cells. Analysis of p53 protein expression and of its downstream transcription targets, p21 and BAX, revealed a p53 associated growth arrest within 5 hours of extract treatment and apoptosis within 24 hours. DNA double strand breaks measured as ?-H2AX were detected early in both MCF-7 and MDA-MB-231 cells. However, loss of cell viability was only partly due to a p53-driven response; as MDA-MB-231 and p53-knockdown MCF-7 cells both underwent cell cycle arrest and death following extract treatment. p53-independent growth arrest and cytotoxicity following DNA damage has been previously ascribed to FOXO3a expression. Here, in MCF-7 and MDA-MB-231 cells, FOXO3a expression was increased significantly within 3 hours of extract treatment and FOXO3 siRNA reduced the extract-induced loss of cell viability in both cell lines.Conclusions/significanceOur results demonstrate for the first time that an aqueous extract of Fagonia cretica can induce cell cycle arrest and apoptosis via p53-dependent and independent mechanisms, with activation of the DNA damage response. We also show that FOXO3a is required for activity in the absence of p53. Our findings indicate that Fagonia cretica aqueous extract contains potential anti-cancer agents acting either singly or in combination against breast cancer cell proliferation via DNA damage-induced FOXO3a and p53 expression.

Dataset Information

Cytosolic Extract of Human Adipose Stem Cells Reverses the Amyloid Beta-Induced Mitochondrial Apoptosis via P53/Foxo3a Pathway.

Publications

Cytosolic Extract of Human Adipose Stem Cells Reverses the Amyloid Beta-Induced Mitochondrial Apoptosis via P53/Foxo3a Pathway.

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