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Doxycycline alters metabolism and proliferation of human cell lines

ABSTRACT: The tetracycline antibiotics are widely used in biomedical research as mediators of inducible gene expression systems. Despite many known effects of tetracyclines on mammalian cells -- including inhibition of the mitochondrial ribosome -- there have been few reports on potential off-target effects at concentrations commonly used in inducible systems. Here, we report that in human cell lines, commonly used concentrations of doxycycline change gene expression patterns and concomitantly shift metabolism towards a more glycolytic phenotype, evidenced by increased lactate secretion and reduced oxygen consumption. We also show that these concentrations are sufficient to slow proliferation and alter cell cycle progression in vitro. These findings suggest that researchers using doxycycline in inducible expression systems should design appropriate controls to account for potential confounding effects of the drug on cellular metabolism.

ORGANISM(S): Homo sapiens

PROVIDER: GSE45029 | GEO | 2013/04/22

SECONDARY ACCESSION(S): PRJNA192857

REPOSITORIES: GEO

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Doxycycline alters metabolism and proliferation of human cell lines

Project description:The tetracycline antibiotics are widely used in biomedical research as mediators of inducible gene expression systems. Despite many known effects of tetracyclines on mammalian cells -- including inhibition of the mitochondrial ribosome -- there have been few reports on potential off-target effects at concentrations commonly used in inducible systems. Here, we report that in human cell lines, commonly used concentrations of doxycycline change gene expression patterns and concomitantly shift metabolism towards a more glycolytic phenotype, evidenced by increased lactate secretion and reduced oxygen consumption. We also show that these concentrations are sufficient to slow proliferation and alter cell cycle progression in vitro. These findings suggest that researchers using doxycycline in inducible expression systems should design appropriate controls to account for potential confounding effects of the drug on cellular metabolism. Total RNA was extracted from MCF12A cells treated with either vehicle control or Dox at 1 ug/mL. The experiment was performed in biological triplicate. Microarray results were processed using the RMA method.

2013-04-22 | E-GEOD-45029 | biostudies-arrayexpress

MCF7 tet-off cells treated or not with 80 ng/ml doxycycline for 12d

Project description:Tet-on and tet-off systems are among the most popular vector systems for inducible transgene expression in mammalian cells. In tet-regulated systems the expression of the transgene depends on the presence or absence of the antibiotic tetracycline or its derivative doxycycline, which are added to the cell culture medium in concentrations considered to be far below cytotoxic levels. Therefore, potential effects on the treated cells, which are exerted by the antibiotic itself and unrelated to transgene expression, are often ignored. We examined the influence of low dose doxycycline on the transcriptional profile of two independent clones of MCF7 human breast carcinoma cells, transfected with tet-off regulator and response plasmids but not harboring any transgene. Treatment with 80 ng/ml doxycycline for 12 days markedly altered gene expression in these cells. Many genes associated with interferon-signaling were up-regulated while cell cycle-associated genes were down-regulated, which was also accompanied by a reduction of cell growth. These results highlight the importance of appropriate controls when working with tet-regulated gene expression systems, to allow distinction between the effects of transgene expression and potential “side effects” of the antibiotic used for its regulation.

2011-05-20 | GSE13926 | GEO

RNA-seq of human melanoma cell line A375 treated with the tetracycline analogs Col-3 or doxycycline against untreated controls

Project description:Apart from their antibacterial activity, tetracyclines have demonstrated diverse and beneficial “off-target” biological activities in human disease, spurring interest in their development as non-antimicrobial therapeutics in diseases such as cancer. To better define biological pathways modified by the tetracyclines in human cancer, we sought to determine differential gene expression in the A375 cancer cell line treated with the tetracyclines, Col-3 and doxycycline, relative to control (vehicle-treated) cells. A375 cells were treated with either 10 μM Col-3, 10 μM doxycycline, or vehicle (DMSO) for 6 h, and changes to gene expression were assessed by RNA-Seq.

2018-09-01 | E-MTAB-7126 | biostudies-arrayexpress

Molecular Basis of Tropheryma whipplei Doxycycline Susceptibility Examined by Transcriptional Profiling

Project description:The suceptibility of T. whipplei to doxycycline was investigated at the transcriptional level using a whole-genome DNA microarray. The microarray data showed good agreement with real-time quantitative PCR (R = 0.969). Exposure of T. whipplei with the subinhibitory concentration of doxycycline allowed to observe antibiotic-specific primary expression profiles, while indirect effects were detected with a 10 times higher concencentration. In contrast to what was observed for several microorganisms exposed to antibiotics, the heat-shock proteins were not affected by the exposure of T. whipplei to doxycycline. Consistent with the mode of action of this translation inhibitor, genes encoding for ribosomal proteins and translation factors were differentially transcribed. This analysis also evidenced the regulation of genes that should account for the cell growth arrest. Long-term survival of nonreplicating bacteria is likely to be ensured by an increased level of ppGpp, the nucleotide effector of the stringent response. Gene expression profile to the higher concentrations of doxycycline was mainly characterized by the up-regulation of ABC transporters that possibly form efflux and detoxification systems, through which T. whipplei may limit the effects of this bacteriostatic compound. This work represents the first comprehensive genomic approach providing insight into the expression signature triggered by the exposure of this bacterial pathogen to antibiotics. Keywords: Antibiotic stress with Doxycycline

2006-09-07 | GSE5717 | GEO

Tetracyclines Specifically Target the Apicoplast of the Malaria Parasite Plasmodium falciparum

Project description:Tetracyclines are effective but slow-acting antimalarial drugs whose mechanism of action remains uncertain. To characterize the antimalarial mechanism of tetracyclines, we evaluated their stage-specific activities, impacts on parasite transcription, and effects on two predicted organelle targets, the apicoplast and the mitochondrion, in cultured Plasmodium falciparum. Antimalarial effects were much greater after two 48-h life cycles than after one cycle, even if the drugs were removed at the end of the first cycle. Doxycycline-treated parasites appeared morphologically normal until late in the second cycle of treatment but failed to develop into merozoites. Doxycycline specifically impaired the expression of apicoplast genes. Apicoplast morphology initially appeared normal in the presence of doxycycline. However, apicoplasts were abnormal in the progeny of doxycycline-treated parasites, as evidenced by a block in apicoplast genome replication, a lack of processing of an apicoplast-targeted protein, and failure to elongate and segregate during schizogeny. Replication of the nuclear and mitochondrial genomes and mitochondrial morphology appeared normal. Our results demonstrate that tetracyclines specifically block expression of the apicoplast genome, resulting in the distribution of nonfunctional apicoplasts into daughter merozoites. The loss of apicoplast function in the progeny of treated parasites leads to a slow but potent antimalarial effect. Keywords: Plasmodium falciparum treated with Doxycycline

2006-07-11 | GSE5267 | GEO

Total RNAseq of K562 cells with a doxycycline-inducible U2AF1S34F or U2AF1WT

Project description:Mutations in the splicing factor gene U2AF1 are relatively common in myelodysplastic neoplasms (MDS) and are associated with an inferior prognosis, but the molecular mechanisms underlying this are not fully elucidated. Circular RNAs (circRNAs) have been implicated in cancer, but it is unknown how mutations in splicing factors may impact on circRNA biogenesis. Here, we used RNA-sequencing to investigate the effects of U2AF1 mutations on circRNA expression in K562 cells with doxycycline-inducible U2AF1S34F or U2AF1WT.

2024-01-29 | GSE224576 | GEO

Tetracyclines Specifically Target the Apicoplast of the Malaria Parasite Plasmodium falciparum

Project description:Tetracyclines are effective but slow-acting antimalarial drugs whose mechanism of action remains uncertain. To characterize the antimalarial mechanism of tetracyclines, we evaluated their stage-specific activities, impacts on parasite transcription, and effects on two predicted organelle targets, the apicoplast and the mitochondrion, in cultured Plasmodium falciparum. Antimalarial effects were much greater after two 48-h life cycles than after one cycle, even if the drugs were removed at the end of the first cycle. Doxycycline-treated parasites appeared morphologically normal until late in the second cycle of treatment but failed to develop into merozoites. Doxycycline specifically impaired the expression of apicoplast genes. Apicoplast morphology initially appeared normal in the presence of doxycycline. However, apicoplasts were abnormal in the progeny of doxycycline-treated parasites, as evidenced by a block in apicoplast genome replication, a lack of processing of an apicoplast-targeted protein, and failure to elongate and segregate during schizogeny. Replication of the nuclear and mitochondrial genomes and mitochondrial morphology appeared normal. Our results demonstrate that tetracyclines specifically block expression of the apicoplast genome, resulting in the distribution of nonfunctional apicoplasts into daughter merozoites. The loss of apicoplast function in the progeny of treated parasites leads to a slow but potent antimalarial effect. We analyzed a series of 12 microarrays covering 55 hours of Plasmodium falciparum treated with doxycycline and 12 microarrays covering the same 55 hours with no doxycycline treatment

2010-07-01 | E-GEOD-5267 | biostudies-arrayexpress

Doxycycline alters porcine renal proteome and degradome during hypothermic machine perfusion

Project description:Ischemia/reperfusion injury (IRI) is a hallmark of tissue injury in donation after circulatory death (DCD) kidneys. The implementation of hypothermic machine perfusion (HMP) provides a platform for repair of DCD kidneys. Doxycycline administration has shown protective effects during IRI. Here, we explore the impact of doxycycline on proteolytic degradation mechanisms and the urinary proteome of perfused kidney grafts. Porcine kidneys underwent 30 min of warm ischemia, 24 h of oxygenated HMP (control/doxycycline) and 240 min of ex-vivo reperfusion. A high-efficiency undecanal-based N-termini enrichment workflow (HUNTER) was performed to identify the tissue degradome. In addition, a proteomic analysis was applied on urine samples collected during reperfusion using label-free quantitation (LFQ) mass spectrometry. Hierarchical clustering showed distinctive clustering profiles between urine samples collected at T15 min (metabolism) and T240 min (complement and coagulation). At T10, significantly more degraded proteins were observed in perfusates of the control group. At T240, significantly more degraded proteins were observed in the doxycycline group, indicating that doxycycline alters protein degradation during HMP. In conclusion, doxycycline administration during HMP led to significant proteomic differences including protective effects by attenuating urinary NGAL levels. Ultimately, we unravelled multiple pathways that undergo alterations during machine perfusion that can be targeted to attenuate IRI induced injury.

2022-08-12 | PXD029599 | Pride

Effect of IDH1 mutation induced by doxycycline on gene expression during VSVΔ51 infection in LN-229-TRE-R132H glioblastoma cells

Project description:To investigate whether IDH1 mutation influence the effects of oncolytic virus VSVΔ51, we transduced doxycycline-inducible IDH1-R132H lentiviruses into LN-229 to establish the LN-229-TRE-R132H cell line. We then performed gene expression profiling analysis using data obtained from RNA-seq of LN-229-TRE-R132H cells infected with or without VSVΔ51 in the presence or absence of IDH1 mutation induced by doxycycline.

2023-09-19 | GSE208634 | GEO

Phase II Trial of Doxycycline with Radiotherapy for Rectal Cancer

Project description:Interventions: Doxycycline is a broad-spectrum antibiotic, which prevents the binding of amino-acyltRNA to the messenger RNA-30S ribosomal subunit, preventing polyribosome formation. It is approved in New Zealand for the treatment of chronic prostatitis, sinusitis, syphilis, pelvic inflammatory disease, malaria, recurrent aphthous ulceration, and acne vulgaris. Doxycycline primarily exerts it’s antimicrobial action by bacteriostasis. It also has antinflammatory effects. Doxycycline will be administered as two 100mg tablets orally each morning, starting two days prior to the first dose of short-course radiotherapy (SCRT), until one day prior to surgery for rectal cancer. Surgery will be performed within three weeks of starting radiotherapy treatment. The duration of doxycycline will be between 12 and 23 days, and will be determined by each participant s individual treatment schedule. Adherence will be assessed through a combination of a patient diary, and count of the number of tablets remaining in the drug container on the patients admission for rectal cancer surgery. Primary outcome(s): Difference in the mean immunohistochemistry (IHC) H-scores for CD133 in resected tumours between the doxycycline and control groups.[Based on rectal cancers surgically resected within 3 weeks of radiotherapy.] Study Design: Purpose: Treatment; Allocation: Non-randomised trial; Masking: Open (masking not used);Type of endpoint: Safety/efficacy

| 2471032 | ecrin-mdr-crc

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