Redox-associated miRNAs regulated by anti-TNBC compounds DET and DETD-35 in MDA-MB-231 cells
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE180000 | GEO | 2024/07/13
REPOSITORIES: GEO
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Project description:Redox-associated miRNAs regulated by anti-TNBC compounds DET and DETD-35 in MDA-MB-231 cells
| PRJNA746246 | ENA
Project description:Introduction: The flavonoid myricetin has been shown to induce cell cycle arrest and mitochondrial-dependent apoptosis in preclinical cancer models. We hypothesised that myricetin-derived flavonoids with redox properties and improved physicochemical attributes that enhance cell uptake and mitochondrial targeting might have increased potential as antitumour agents, since mitochondria are the main site of production of reactive oxygen species (ROS) and redox status is known to regulate the development and advancement of certain cancers. In this study we assessed a small library of novel flavonoids, then focussed on the lead compound, second-generation analogue OncamexTM, its mechanism of action and structure-activity relationships as an anti-proliferative agent. Methods: With this aim, we studied the effect of OncamexTM in a panel of 7 breast cancer cell lines using proliferation, cytotoxicity and apoptosis assays. The redox properties and mitochondrial delivery of the drug were studied using cyclic voltammetry and fluorescence microscopy, respectively. The mechanism of action was further studied using western blotting, gene expression analysis and immunohistochemistry (IHC) of treated xenograft tissue from in vivo mice models. Results: Sulforhodamine B (SRB) proliferation assays demonstrated strong, anti-proliferative properties of OncamexTM, with IC50 values in the low micromolar range. Treatment for 8 h exerted concentration-dependent reduction in cell viability and induction of cytotoxicity and apoptosis, with increased caspase activation. Microarray analysis suggested that OncamexTM regulates changes in cell cycle and apoptosis at gene expression level. Fluorescence microscopy was used to investigate mitochondrial targeting and ROS regulation in treated cells. OncamexTM was found to induce production of superoxide at concentrations which exerted anti-proliferative effects. Initial in vivo studies in mice implanted with a MDA-MB-231 breast cancer xenograft showed that OncamexTM inhibited tumour growth, reducing tissue viability and Ki-67 proliferation, with no overall systemic toxicity. Conclusions: OncamexTM is a novel flavonoid capable of specific delivery to the mitochondria and induction of ROS production. We have shown its antitumor activity in preclinical models of breast cancer, both in vitro and in initial in vivo models, where tumour growth was arrested without inducing toxicity, support the potential of this novel drug for its continued development as an anticancer agent. Total RNA was obtained from 5 breast cancer cell lines subjected to 6 hours of 10µM OncamexTM and matched untreated controls (1% DMSO)
2015-09-01 | E-GEOD-70949 | biostudies-arrayexpress
Project description:Transcription signatures have been used to stratify breast cancer patients into clinically distinct subgroups. However, transcription alone does not determine protein expression. Of potentially equal importance for determining the tumor phenotype is the rate at which transcripts are translated to form protein. Protein translation is controlled to a major degree by miRNA, and cancer cells may deregulate the expression of key genes by altering the activity of relevant miRNAs. The importance of miRNA deregulation and the extent to which multiple miRNAs coordinately deregulate key proteins in breast cancer is only partly understood. To gain such insight, we analyzed genome-wide miRNA expression and mRNA/protein expression for a panel of 105 selected cancer related genes in breast carcinomas from 283 patients. The miRNA-mRNA-protein interactome for the selected genes was constructed by modeling protein expression as a joint function of mRNA and miRNA expression, considering the effect of both one miRNA at a time, and all studied miRNAs simultaneously. The interactome represents a map of the global effects of miRNAs on protein expression, capturing direct as well as indirect effects. The results reveal extensive association between miRNA and protein expression as well as coordinated effects of multiple miRNAs on individual proteins. Applying the model onto two other independent primary breast cancer cohorts confirmed the generalizability of key aspects of the interactome map. The mRNA expression profiling of 283 breast cancer samples was performed using the SurePrint G3 Human GE 8x60K one-color microarrays from Agilent (Agilent Technologies, Santa Clara, CA, USA) according to the manufacturer’s protocol (One-Color Microarray-Based Gene Expression Analysis, Low Input Quick Amp Labeling, v.6.5, May 2010). For each sample, 100 ng of RNA was amplified and hybridized on the array. Scanning was performed with Agilent Scanner G2565A, using AgilentG3_GX_1Color as profile. Signals were extracted using FE v.10.7.3.1 and protocol GE1_107_Sep09 (Agilent Technologies). Arrays were log2-transformed, quantile normalized and hospital-adjusted by subtracting from each probe value the mean probe value among samples from the same hospital. The Oslo Breast Cancer Consortium (OSBREAC)
2015-02-02 | E-GEOD-58212 | biostudies-arrayexpress
Project description:Transcription signatures have been used to stratify breast cancer patients into clinically distinct subgroups. However, transcription alone does not determine protein expression. Of potentially equal importance for determining the tumor phenotype is the rate at which transcripts are translated to form protein. Protein translation is controlled to a major degree by miRNA, and cancer cells may deregulate the expression of key genes by altering the activity of relevant miRNAs. The importance of miRNA deregulation and the extent to which multiple miRNAs coordinately deregulate key proteins in breast cancer is only partly understood. To gain such insight, we analyzed genome-wide miRNA expression and mRNA/protein expression for a panel of 105 selected cancer related genes in breast carcinomas from 283 patients. The miRNA-mRNA-protein interactome for the selected genes was constructed by modeling protein expression as a joint function of mRNA and miRNA expression, considering the effect of both one miRNA at a time, and all studied miRNAs simultaneously. The interactome represents a map of the global effects of miRNAs on protein expression, capturing direct as well as indirect effects. The results reveal extensive association between miRNA and protein expression as well as coordinated effects of multiple miRNAs on individual proteins. Applying the model onto two other independent primary breast cancer cohorts confirmed the generalizability of key aspects of the interactome map. The miRNA expression profiling of 283 breast cancer samples was performed using the 8x15k “Human miRNA Microarray Kit release 14.0 (V2)” with design id 029297 from Agilent (Agilent Technologies, Santa Clara, CA, USA). In brief, 100 ng total RNA was dephosphorylated, labeled and hybridized for 20 hours, following the manufacturer’s protocol. Scanning was performed on Agilent Scanner G2565A, signals were extracted using Feature Extraction v10.7.3.1 and the subsequent data processing was performed using the GeneSpring software v11.0 (Agilent Technologies). In brief, the miRNA signal intensities were log2-transformed and normalized to the 90th percentile, and miRNAs that were detected in less than 10% of the samples were excluded. This resulted in 421 unique mature miRNAs. The Oslo Breast Cancer Consortium (OSBREAC)
2015-02-02 | E-GEOD-58210 | biostudies-arrayexpress
Project description:Oxidative stress illustrates an imbalance between radical formation and removal. Frequent redox stress is critically involved in a variety of human pathologies including cancer, psoriasis, and chronic wounds. However, reactive species pursue a dual role being involved in signaling on the one hand and oxidative damage on the other. Using a HaCaT keratinocyte cell culture model, we here aimed at investigating the cellular and transcriptional response to periodic, low dose oxidative challenge over three months. Chronic redox stress was generated by frequent incubation with cold physical plasma treated cell culture medium. Using mRNA microarray technology, we found both acute ROS stress responses as well as numerous adaptions on the transcriptional level and over several weeks of redox challenge. This included an altered expression of 260 genes that function in inflammation and redox homeostasis, such as, signaling molecules, cytokines, and anti-oxidant enzymes. Apoptotic signaling was affected to a minor extend, especially in p53 down-stream targets. Strikingly, the anti-apoptotic heat shock protein HSP27 was strongly upregulated. These results suggest a variety of adaptive responses relating involved a number of cellular processes elicited by frequent redox stress over several months. They may help to better understand inflammatory responses in redox related diseases and possibly allow uncovering new biomarkers of ROS-stress. Microarrays were used to analyze and investigate the biological effects of repeated exposure of cold physical plasma on human HaCaT keratinocytes. Using an argon plasma jet kinpen, regulated transcripts were analyzed and further described in Schmidt et al. (submittes): âLong-term exposure to cold plasma-generated ROS âan in vitro model for redox-related diseases of the skinâ. HaCaT keratinocytes exposed to plasma treated medium - time course
2015-11-11 | E-GEOD-74876 | biostudies-arrayexpress
Project description:Let-7 microRNAs (miRNAs) are a family of highly conserved well-established promoters of terminal differentiation that are expressed in all healthy adult tissues and frequently repressed in cancer cells. The tumour suppressive role of let-7 in a variety of cancers in vitro and in vivo has been widely documented and prompted these miRNAs to be candidate genes for miRNA replacement therapy. Reprogrammed metabolism, recently identified as a new hallmark of cancer, contributes to cancer cell growth, proliferation, invasiveness and drug resistance. In this study we identified a new metabolic role of let-7a in triple-negative breast cancer and metastatic melanoma cell lines. We show that let-7a down-regulates key anabolic enzymes, promotes oxidative phosphorylation and mitochondrial ROS formation accompanied by the up-regulation of the oxidative stress responsive genes. To assess if we could exploit these increased ROS levels for therapeutic purposes, we combined let-7a transfection with the antitumor drug doxorubicin. In both cancer types we observed a stronger response to the doxorubicin treatment in let-7a transfected cells. Pre-treatment with an antioxidant N-acetyl cysteine totally abolished this difference, indicating that the increased doxorubicin sensitivity of let-7a cells depends on the redox pathway. We demonstrated that let-7a plays a prominent role in regulating energy metabolism in cancer cells. We propose that a benefit from let-7 miRNA replacement therapy could come not only from the repression of oncogenic pathways targeted directly by let-7, but also by increased sensitivity to chemotherapeutic agents through indirect metabolic changes caused by let-7. Investigation of let-7a metabolic role in breast cancer and melanoma cells.
2015-12-31 | E-GEOD-60326 | biostudies-arrayexpress
Project description:Introduction: The flavonoid myricetin has been shown to induce cell cycle arrest and mitochondrial-dependent apoptosis in preclinical cancer models. We hypothesised that myricetin-derived flavonoids with redox properties and improved physicochemical attributes that enhance cell uptake and mitochondrial targeting might have increased potential as antitumour agents, since mitochondria are the main site of production of reactive oxygen species (ROS) and redox status is known to regulate the development and advancement of certain cancers. In this study we assessed a small library of novel flavonoids, then focussed on the lead compound, second-generation analogue OncamexTM, its mechanism of action and structure-activity relationships as an anti-proliferative agent. Methods: With this aim, we studied the effect of OncamexTM in a panel of 7 breast cancer cell lines using proliferation, cytotoxicity and apoptosis assays. The redox properties and mitochondrial delivery of the drug were studied using cyclic voltammetry and fluorescence microscopy, respectively. The mechanism of action was further studied using western blotting, gene expression analysis and immunohistochemistry (IHC) of treated xenograft tissue from in vivo mice models. Results: Sulforhodamine B (SRB) proliferation assays demonstrated strong, anti-proliferative properties of OncamexTM, with IC50 values in the low micromolar range. Treatment for 8 h exerted concentration-dependent reduction in cell viability and induction of cytotoxicity and apoptosis, with increased caspase activation. Microarray analysis suggested that OncamexTM regulates changes in cell cycle and apoptosis at gene expression level. Fluorescence microscopy was used to investigate mitochondrial targeting and ROS regulation in treated cells. OncamexTM was found to induce production of superoxide at concentrations which exerted anti-proliferative effects. Initial in vivo studies in mice implanted with a MDA-MB-231 breast cancer xenograft showed that OncamexTM inhibited tumour growth, reducing tissue viability and Ki-67 proliferation, with no overall systemic toxicity. Conclusions: OncamexTM is a novel flavonoid capable of specific delivery to the mitochondria and induction of ROS production. We have shown its antitumor activity in preclinical models of breast cancer, both in vitro and in initial in vivo models, where tumour growth was arrested without inducing toxicity, support the potential of this novel drug for its continued development as an anticancer agent.
2015-09-01 | GSE70949 | GEO
Project description:Oxidative stress illustrates an imbalance between radical formation and removal. Frequent redox stress is critically involved in a variety of human pathologies including cancer, psoriasis, and chronic wounds. However, reactive species pursue a dual role being involved in signaling on the one hand and oxidative damage on the other. Using a HaCaT keratinocyte cell culture model, we here aimed at investigating the cellular and transcriptional response to periodic, low dose oxidative challenge over three months. Chronic redox stress was generated by frequent incubation with cold physical plasma treated cell culture medium. Using mRNA microarray technology, we found both acute ROS stress responses as well as numerous adaptions on the transcriptional level and over several weeks of redox challenge. This included an altered expression of 260 genes that function in inflammation and redox homeostasis, such as, signaling molecules, cytokines, and anti-oxidant enzymes. Apoptotic signaling was affected to a minor extend, especially in p53 down-stream targets. Strikingly, the anti-apoptotic heat shock protein HSP27 was strongly upregulated. These results suggest a variety of adaptive responses relating involved a number of cellular processes elicited by frequent redox stress over several months. They may help to better understand inflammatory responses in redox related diseases and possibly allow uncovering new biomarkers of ROS-stress. Microarrays were used to analyze and investigate the biological effects of repeated exposure of cold physical plasma on human HaCaT keratinocytes. Using an argon plasma jet kinpen, regulated transcripts were analyzed and further described in Schmidt et al. (submittes): “Long-term exposure to cold plasma-generated ROS –an in vitro model for redox-related diseases of the skin”.
2015-11-11 | GSE74876 | GEO
Project description:Identification for microRNA signatures to predict breast cancer recurrence in young women were performed through expression profiling of a total 2565 miRNAs in 45 samples diagnosed as invasive ducatal carcinoma of no special type (NST) cases which had been consecutively operated on within a defined short period of time.
2017-11-22 | GSE97811 | GEO
Project description:Metastatic breast cancer cells disseminate to organs with a soft microenvironment. Whether and how tissue mechanical properties influence their response to treatment remains unclear. Here we found that a soft ECM empowers redox homeostasis. Cells cultured on a soft ECM display increased peri-mitochondrial F-actin promoted by Spire1C and Arp2/3 nucleation factors, and increased DRP1- and MIEF1/2-dependent mitochondrial fission. Changes in mitochondrial dynamics lead to increased mtROS production and activate the NRF2 antioxidant transcriptional response, including increased cystine uptake and glutathione metabolism. This retrograde response endows cells with resistance to oxidative stress and ROS-dependent chemotherapy drugs. This is relevant in a mouse model of metastatic breast cancer cells dormant in the lung soft tissue, where inhibition of DRP1 and NRF2 restored cisplatin sensitivity and prevented disseminated cancer cell awakening. We propose that targeting this mitochondrial dynamics- and redox-based mechanotransduction pathway could open new avenues to prevent metastatic relapse.
2021-12-21 | GSE189803 | GEO