Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1209960 | ENA |
REPOSITORIES: ENA
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Project description:The lack of a cure for metastatic prostate cancer (PCa) highlights the urgent need for more efficient drugs to fight this disease. Here, we report the molecular mechanism of action of the natural product 6-acetoxy-anopterine (6-AA) in malignant cells of the prostate. This potent cytotoxic alkaloid from the endemic Australian tree Anopterus macleayanus induced at low nanomolar doses a strong accumulation of LNCaP and PC3 PCa cells in mitosis, severe mitotic spindle defects and asymmetric cell divisions, ultimately leading to mitotic catastrophe accompanied by cell death through apoptosis. DNA microarray of 6-AA treated LNCaP cells combined with pathway analysis identified very similar transcriptional changes when compared to vinblastine, highlighting pathways involved in mitosis, microtubule spindle organisation and microtubule binding. Like vinblastine, 6-AA inhibited microtubule polymerization in a cell-free system and reduced microtubule polymer mass in vitro. Yet, microtubule alterations that are associated with resistance to microtubule-destabilizing drugs like vinca alkaloids or 2-methoxyestradiol did not confer cross-resistance to 6-AA, suggesting a different mechanism of microtubule interaction. Finally, 6-AA is the first-in-class microtubule inhibitor that features the unique anopterine scaffold. Altogether, this study provides a strong rationale to further develop this novel structure class of microtubule inhibitor for the treatment of malignant disease.
2016-05-11 | GSE81277 | GEO
Project description:Microtubule targeting agents (MTAs) have been used for the treatment of cancer for many decades and are among the most successful chemotherapeutic agents. However, their application and effectiveness is limited because of toxicity and resistance as well as a lack of knowledge of molecular mechanisms downstream of microtubule inhibition. Insight into key pathways that link microtubule disruption to cell death is critical for optimal use of these drugs, for defining biomarkers useful in patient stratification, and for informed design of drug combinations. Although MTAs characteristically induce death in mitosis, microtubule destabilizing agents such as vincristine also induce death directly in G1 phase in primary acute lymphoblastic leukemia (ALL) cells. Because many signaling pathways regulating cell survival and death involve changes in protein expression and phosphorylation, we undertook a comprehensive quantitative proteomic study of G1 phase ALL cells treated with vincristine. The results revealed distinct alterations associated with c-Jun N-terminal kinase signaling, anti-proliferative signaling, the DNA damage response, and cytoskeletal remodeling. Signals specifically associated with cell death were identified by pre-treatment with the CDK4/6 inhibitor palbociclib, which caused G1 arrest and precluded death induction. These results provide insight into signaling mechanisms regulating cellular responses to microtubule inhibition, and provide a foundation for a better understanding of the clinical mechanisms of MTAs and for the design of novel drug combinations.
2021-12-30 | PXD027190 | Pride
Project description:The goal of this study is to compare gene expression profiles in quiescent RPE1 hTert cells treated with microtubule-stabilizing (paclitaxel) and microtubule-destabilizing poisons (combretastatin A4)
2019-03-19 | GSE128414 | GEO
Project description:In a genome-wide CRISPR-Cas9 resistance drug screen, we identified the master osmostress regulator WNK1 kinase as a modulator of the response to the mitotic drug rigosertib. Osmotic stress and WNK1 inactivation lead to an altered response not only to rigosertib but also to other microtubule-related drugs, minimizing the prototypical mitotic arrest produced by these drugs. This effect is due to an alteration in microtubule stability and polymerization dynamics, likely maintained by fluctuations in intracellular molecular crowding upon WNK1 inactivation. This promotes resistance to microtubule depolymerizing drugs, and increased sensitivity to microtubule stabilizing drugs. In summary, our data proposes WNK1 osmoregulation activity as a biomarker for microtubule-associated chemotherapy response.
2024-07-16 | GSE271314 | GEO
Project description:This study is a comparative analysis to examine whether there are significant gene expression changes after 6 hours of treatment with three diverse microtubule destabilizers: combretastation A4 (CA4), vinblastine (VB), and plinabulin (PL). Other comparators include baseline control DMSO, microtubule destabilizer docetaxel (DTXL), and inflammatory cytokine TNF-α. We use primary human pulmonary microvascular endothelial cells as a model for a cell sensitive to microtubule perturbations.
2025-01-25 | GSE286439 | GEO
Project description:Andrew Koo, David Nordsletten, Renato Umeton, Beracah Yankama, Shiva Ayyadurai, Guillermo García-Cardeña & C. Forbes Dewey. In silico modeling of shear-stress-induced nitric oxide production in endothelial cells through systems biology. Biophysical Journal 104, 10 (2013).
Nitric oxide (NO) produced by vascular endothelial cells is a potent vasodilator and an antiinflammatory mediator. Regulating production of endothelial-derived NO is a complex undertaking, involving multiple signaling and genetic pathways that are activated by diverse humoral and biomechanical stimuli. To gain a thorough understanding of the rich diversity of responses observed experimentally, it is necessary to account for an ensemble of these pathways acting simultaneously. In this article, we have assembled four quantitative molecular pathways previously proposed for shear-stress-induced NO production. In these pathways, endothelial NO synthase is activated 1), via calcium release, 2), via phosphorylation reactions, and 3), via enhanced protein expression. To these activation pathways, we have added a fourth, a pathway describing actual NO production from endothelial NO synthase and its various protein partners. These pathways were combined and simulated using CytoSolve, a computational environment for combining independent pathway calculations. The integrated model is able to describe the experimentally observed change in NO production with time after the application of fluid shear stress. This model can also be used to predict the specific effects on the system after interventional pharmacological or genetic changes. Importantly, this model reflects the up-to-date understanding of the NO system, providing a platform upon which information can be aggregated in an additive way.
2024-09-02 | BIOMD0000000468 | BioModels
Project description:Andrew Koo, David Nordsletten, Renato Umeton, Beracah Yankama, Shiva Ayyadurai, Guillermo García-Cardeña & C. Forbes Dewey. In silico modeling of shear-stress-induced nitric oxide production in endothelial cells through systems biology. Biophysical Journal 104, 10 (2013).
Nitric oxide (NO) produced by vascular endothelial cells is a potent vasodilator and an antiinflammatory mediator. Regulating production of endothelial-derived NO is a complex undertaking, involving multiple signaling and genetic pathways that are activated by diverse humoral and biomechanical stimuli. To gain a thorough understanding of the rich diversity of responses observed experimentally, it is necessary to account for an ensemble of these pathways acting simultaneously. In this article, we have assembled four quantitative molecular pathways previously proposed for shear-stress-induced NO production. In these pathways, endothelial NO synthase is activated 1), via calcium release, 2), via phosphorylation reactions, and 3), via enhanced protein expression. To these activation pathways, we have added a fourth, a pathway describing actual NO production from endothelial NO synthase and its various protein partners. These pathways were combined and simulated using CytoSolve, a computational environment for combining independent pathway calculations. The integrated model is able to describe the experimentally observed change in NO production with time after the application of fluid shear stress. This model can also be used to predict the specific effects on the system after interventional pharmacological or genetic changes. Importantly, this model reflects the up-to-date understanding of the NO system, providing a platform upon which information can be aggregated in an additive way.
2024-09-02 | BIOMD0000000464 | BioModels
Project description:Andrew Koo, David Nordsletten, Renato Umeton, Beracah Yankama, Shiva Ayyadurai, Guillermo García-Cardeña & C. Forbes Dewey. In silico modeling of shear-stress-induced nitric oxide production in endothelial cells through systems biology. Biophysical Journal 104, 10 (2013).
Nitric oxide (NO) produced by vascular endothelial cells is a potent vasodilator and an antiinflammatory mediator. Regulating production of endothelial-derived NO is a complex undertaking, involving multiple signaling and genetic pathways that are activated by diverse humoral and biomechanical stimuli. To gain a thorough understanding of the rich diversity of responses observed experimentally, it is necessary to account for an ensemble of these pathways acting simultaneously. In this article, we have assembled four quantitative molecular pathways previously proposed for shear-stress-induced NO production. In these pathways, endothelial NO synthase is activated 1), via calcium release, 2), via phosphorylation reactions, and 3), via enhanced protein expression. To these activation pathways, we have added a fourth, a pathway describing actual NO production from endothelial NO synthase and its various protein partners. These pathways were combined and simulated using CytoSolve, a computational environment for combining independent pathway calculations. The integrated model is able to describe the experimentally observed change in NO production with time after the application of fluid shear stress. This model can also be used to predict the specific effects on the system after interventional pharmacological or genetic changes. Importantly, this model reflects the up-to-date understanding of the NO system, providing a platform upon which information can be aggregated in an additive way.
2024-09-02 | BIOMD0000000465 | BioModels
Project description:Andrew Koo, David Nordsletten, Renato Umeton, Beracah Yankama, Shiva Ayyadurai, Guillermo García-Cardeña & C. Forbes Dewey. In silico modeling of shear-stress-induced nitric oxide production in endothelial cells through systems biology. Biophysical Journal 104, 10 (2013).
Nitric oxide (NO) produced by vascular endothelial cells is a potent vasodilator and an antiinflammatory mediator. Regulating production of endothelial-derived NO is a complex undertaking, involving multiple signaling and genetic pathways that are activated by diverse humoral and biomechanical stimuli. To gain a thorough understanding of the rich diversity of responses observed experimentally, it is necessary to account for an ensemble of these pathways acting simultaneously. In this article, we have assembled four quantitative molecular pathways previously proposed for shear-stress-induced NO production. In these pathways, endothelial NO synthase is activated 1), via calcium release, 2), via phosphorylation reactions, and 3), via enhanced protein expression. To these activation pathways, we have added a fourth, a pathway describing actual NO production from endothelial NO synthase and its various protein partners. These pathways were combined and simulated using CytoSolve, a computational environment for combining independent pathway calculations. The integrated model is able to describe the experimentally observed change in NO production with time after the application of fluid shear stress. This model can also be used to predict the specific effects on the system after interventional pharmacological or genetic changes. Importantly, this model reflects the up-to-date understanding of the NO system, providing a platform upon which information can be aggregated in an additive way.
2024-09-02 | BIOMD0000000466 | BioModels
Project description:Andrew Koo, David Nordsletten, Renato Umeton, Beracah Yankama, Shiva Ayyadurai, Guillermo García-Cardeña & C. Forbes Dewey. In silico modeling of shear-stress-induced nitric oxide production in endothelial cells through systems biology. Biophysical Journal 104, 10 (2013).
Nitric oxide (NO) produced by vascular endothelial cells is a potent vasodilator and an antiinflammatory mediator. Regulating production of endothelial-derived NO is a complex undertaking, involving multiple signaling and genetic pathways that are activated by diverse humoral and biomechanical stimuli. To gain a thorough understanding of the rich diversity of responses observed experimentally, it is necessary to account for an ensemble of these pathways acting simultaneously. In this article, we have assembled four quantitative molecular pathways previously proposed for shear-stress-induced NO production. In these pathways, endothelial NO synthase is activated 1), via calcium release, 2), via phosphorylation reactions, and 3), via enhanced protein expression. To these activation pathways, we have added a fourth, a pathway describing actual NO production from endothelial NO synthase and its various protein partners. These pathways were combined and simulated using CytoSolve, a computational environment for combining independent pathway calculations. The integrated model is able to describe the experimentally observed change in NO production with time after the application of fluid shear stress. This model can also be used to predict the specific effects on the system after interventional pharmacological or genetic changes. Importantly, this model reflects the up-to-date understanding of the NO system, providing a platform upon which information can be aggregated in an additive way.
2024-09-02 | BIOMD0000000467 | BioModels