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Inhibition of AK4 expression increases drug sensitivity and elevates mitochondrial ATP synthesis

ABSTRACT: Adenylate kinase 4 (AK4) is localized in the mitochondrial matrix, and is believed to be involved in stress, drug resistance, the malignant transformation of cancer, and ATP regulation. We produced AK4 knockdown HeLa cells by using shRNA and used these to analyze resistance, and found that sensitivity to hypoxia and drugs increased.

ORGANISM(S): Homo sapiens

PROVIDER: GSE61843 | GEO | 2016/03/31

SECONDARY ACCESSION(S): PRJNA262546

REPOSITORIES: GEO

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Inhibition of AK4 expression increases drug sensitivity and elevates mitochondrial ATP synthesis

Project description:Adenylate kinase 4 (AK4) is localized in the mitochondrial matrix, and is believed to be involved in stress, drug resistance, the malignant transformation of cancer, and ATP regulation. We produced AK4 knockdown HeLa cells by using shRNA and used these to analyze resistance, and found that sensitivity to hypoxia and drugs increased. 3 samples of HeLa cells haboring AK4 shRNA plasmids and 4 samples of HeLa cells haboring control shRNA plasmid.

2016-03-31 | E-GEOD-61843 | biostudies-arrayexpress

Adenylate kinase 4 Promotes the expression of Inflammatory Genes in Macrophages via Hif-1a

Project description:Macrophages comprise the first line of defense against various pathogens. Classically activated macrophages (M1), induced by IFNg and LPS, express a high level of inflammatory cytokines and contribute to inflammatory processes. By contrast, alternatively activated macrophages (M2) are induced by IL-4/IL-13, produce IL-10, and display anti-inflammatory activity. Adenylate kinase 4 (Αk4), an enzyme that transfers phosphate group among ATP/GTP, AMP, and ADP, is a key modulator of ATP and is involved in maintaining the homeostasis of cellular nucleotides which is essential for the function of cells. However, its role in regulating the function of macrophages is not fully understood. Here we report that the expression of Ak4 is induced in M1 but not M2 macrophages. Suppressing the expression of Ak4 in M1 macrophages with shRNA enhances the production of ATP. RNA-seq analysis identifies several inflammation-related genes, including Il1b, Il6, Tnfa, Nos2 and Hif1a, as downstream targets of Ak4. We further demonstrate that Ak4 and Hif1a form a positive feedback loop in sustaining the expression of the inflammation-related genes. Our data depict a potential mechanism linking energy consumption and inflammation in macrophages.

2021-04-07 | GSE143302 | GEO

An AMP nucleosidase gene knockout in Escherichia coli elevates intracellular ATP levels and increases cold tolerance.

Project description:Disparate psychrophiles (e.g. glacier ice worms, bacteria, algae and fungi) elevate steady-state intracellular ATP levels as temperatures decline, which has been interpreted as a compensatory mechanism to offset reductions in molecular motion and Gibb's free energy of ATP hydrolysis. In this study, we sought to manipulate steady-state ATP levels in the mesophilic bacterium, Escherichia coli, to investigate the relationship between cold temperature survivability and elevated intracellular ATP. Based on known energetic pathways and feedback loops, we targeted the AMP nucleotidase (amn) gene, which is thought to encode the primary AMP degradative enzyme in prokaryotes. By knocking out amn in wild-type E. coli DY330 cells using recombineering methodology, we generated a mutant (AMNk) that elevated intracellular ATP levels by more than 30% across its viable temperature range. As temperature was lowered, the relative ATP disparity between AMNk and DY330 cells increased to approximately 66% at 10 degrees C, and was approximately 100% after storage at 0 degrees C for 5-7 days. AMNk cells stored at 0 degrees C for 7 days displayed approximately fivefold higher cell viability than wild-type DY330 cells treated in the same manner.

| S-EPMC2412920 | biostudies-literature

Integrated Analysis of Genes Encoding ATP-Dependent Chromatin Remodelers Identifies CHD7 as a Potential Target for Colorectal Cancer Therapy

Project description:We experimentally demonstrated that CHD7 promotes the growth of colorectal cancer cells in vitro and in vivo. Mechanistically, RNA-seq and ATAC-seq approaches together with ChIP assays indicated that CHD7 can bind to the promoters of target genes to maintain chromatin accessibility and facilitate transcription. We found that CHD7 knockdown downregulates AK4 expression and activates AMPK phosphorylation, thereby promoting the phosphorylation and stability of p53 and leading to the inhibition of the colorectal cancer growth. Our genomic analyses of ATPCRs across large-scale cancer specimens identified potential therapeutic targets and our experimental studies revealed a novel CHD7-AK4-AMPK-p53 axis that plays an oncogenic role in colorectal cancer.

2022-01-04 | GSE192905 | GEO

Impairment of vesicular ATP release affects glucose metabolism and increases insulin sensitivity.

Project description:Neuroendocrine cells store ATP in secretory granules and release it along with hormones that may trigger a variety of cellular responses in a process called purinergic chemical transmission. Although the vesicular nucleotide transporter (VNUT) has been shown to be involved in vesicular storage and release of ATP, its physiological relevance in vivo is far less well understood. In Vnut knockout (Vnut(-/-)) mice, we found that the loss of functional VNUT in adrenal chromaffin granules and insulin granules in the islets of Langerhans led to several significant effects. Vesicular ATP accumulation and depolarization-dependent ATP release were absent in the chromaffin granules of Vnut(-/-) mice. Glucose-responsive ATP release was also absent in pancreatic ?-cells in Vnut(-/-) mice, while glucose-responsive insulin secretion was enhanced to a greater extent than that in wild-type tissue. Vnut(-/-) mice exhibited improved glucose tolerance and low blood glucose upon fasting due to increased insulin sensitivity. These results demonstrated an essential role of VNUT in vesicular storage and release of ATP in neuroendocrine cells in vivo and suggest that vesicular ATP and/or its degradation products act as feedback regulators in catecholamine and insulin secretion, thereby regulating blood glucose homeostasis.

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Expression data from AK4 overexpression in CL1-0 lung cancer cell line and AK4 knockdown in CL1-5 lung cancer cell line

Project description:We demonstrate that AK4 down-regulation shRNAs significantly reduced cell migration and invasion in highly invasive lung cancer cell lines in vitro, as well as in lung metastases in vivo We used microarrays to analyze the AK4 regulated gene expression underlying invasion-metastasis cascade. CL1-0 lung adenocarcinoma cells with AK4 overexpression and CL1-5 cells with AK4 knockdown were selected for RNA extraction and hybridization on Affymetrix microarrays.

2012-12-03 | E-GEOD-37903 | biostudies-arrayexpress

Starvation increases insulin sensitivity and reduces juvenile hormone synthesis in mosquitoes.

Project description:BackgroundThe interactions between the insulin signaling pathway (ISP) and juvenile hormone (JH) controlling reproductive trade-offs are well documented in insects. JH and insulin regulate reproductive output in mosquitoes; both hormones are involved in a complex regulatory network, in which they influence each other and in which the mosquito's nutritional status is a crucial determinant of the network's output. Previous studies reported that the insulin-TOR (target of rapamacyn) signaling pathway is involved in the nutritional regulation of JH synthesis in female mosquitoes. The present studies further investigate the regulatory circuitry that controls both JH synthesis and reproductive output in response to nutrient availability.MethodsWe used a combination of diet restriction, RNA interference (RNAi) and insulin treatments to modify insulin signaling and study the cross-talk between insulin and JH in response to starvation. JH synthesis was analyzed using a newly developed assay utilizing fluorescent tags.ConclusionsOur results reveal that starvation decreased JH synthesis via a decrease in insulin signaling in the corpora allata (CA). Paradoxically, starvation-induced up regulation of insulin receptor transcripts and therefore "primed" the gland to respond rapidly to increases in insulin levels. During this response to starvation the synthetic potential of the CA remained unaffected, and the gland rapidly and efficiently responded to insulin stimulation by increasing JH synthesis to rates similar to those of CA from non-starved females.

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Expression data from CCL2 overexpression in MCF7 breast cancer cell line and CCL2 knockdown in MB231 breast cancer cell line.

2022-07-28 | GSE128876 | GEO

Expression data from AK4 overexpression in CL1-0 lung cancer cell line and AK4 knockdown in CL1-5 lung cancer cell line

2012-12-03 | GSE37903 | GEO

Inhibiting phosphatidylcholine remodeling in adipose tissue increases insulin sensitivity [RNA-Seq]

Project description:Cell membrane phosphatidylcholine composition is regulated by lysophosphatidylcholine acyltransferase (LPCAT); changes in membrane phosphatidylcholine saturation are implicated in metabolic disorders. Here, we identified LPCAT3 as the major isoform of LPCAT in adipose tissues and created adipocyte-specific Lpcat3-knockout mice to study adipose tissue lipid metabolism. Transcriptome sequencing and plasma adipokine profiling were used to investigate how LPCAT3 regulates adipose tissue insulin signaling. LPCAT3 deficiency reduced polyunsaturated phosphatidylcholines in adipocyte plasma membranes, increasing insulin sensitivity. LPCAT3 deficiency influenced membrane lipid rafts, which activated insulin receptors and AKT in adipose tissue, and attenuated diet-induced insulin resistance. Conversely, higher LPCAT3 activity in adipose tissues from ob/ob, db/db, and high-fat diet-fed mice reduced insulin signaling. Adding polyunsaturated phosphatidylcholines to mature human or mouse adipocytes in vitro worsened insulin signaling. We suggest that targeting LPCAT3 in adipose tissues to manipulate membrane phospholipid saturation is a new strategy to treat insulin resistance.

2024-07-16 | GSE235302 | GEO

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