scholarly journals A leak pathway for luminal protons in endosomes drives oncogenic signalling in glioblastoma

2015 ◽  
Vol 6 (1) ◽  
Author(s):  
Kalyan C. Kondapalli ◽  
Jose P. Llongueras ◽  
Vivian Capilla-González ◽  
Hari Prasad ◽  
Anniesha Hack ◽  
...  
Keyword(s):  
Leak Pathway ◽  
Oncogenic Signalling

scholarly journals Broccoli Consumption Interacts with GSTM1 to Perturb Oncogenic Signalling Pathways in the Prostate

PLoS ONE ◽  
2008 ◽  
Vol 3 (7) ◽  
pp. e2568 ◽  
Author(s):  
Maria Traka ◽  
Amy V. Gasper ◽  
Antonietta Melchini ◽  
James R. Bacon ◽  
Paul W. Needs ◽  
...  
Keyword(s):  
Signalling Pathways ◽  
Oncogenic Signalling

scholarly journals A systems pharmacology approach based on oncogenic signalling pathways to determine the mechanisms of action of natural products in breast cancer from transcriptome data

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Regan Odongo ◽  
Asuman Demiroglu-Zergeroglu ◽  
Tunahan Çakır
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Complex Diseases ◽  
Mechanisms Of Action ◽  
Signalling Pathways ◽  
Breast Cancer Cell Lines ◽  
Transcriptome Data ◽  
Oncogenic Signalling

Abstract Background Narrow spectrum of action through limited molecular targets and unforeseen drug-related toxicities have been the main reasons for drug failures at the phase I clinical trials in complex diseases. Most plant-derived compounds with medicinal values possess poly-pharmacologic properties with overall good tolerability, and, thus, are appropriate in the management of complex diseases, especially cancers. However, methodological limitations impede attempts to catalogue targeted processes and infer systemic mechanisms of action. While most of the current understanding of these compounds is based on reductive methods, it is increasingly becoming clear that holistic techniques, leveraging current improvements in omic data collection and bioinformatics methods, are better suited for elucidating their systemic effects. Thus, we developed and implemented an integrative systems biology pipeline to study these compounds and reveal their mechanism of actions on breast cancer cell lines. Methods Transcriptome data from compound-treated breast cancer cell lines, representing triple negative (TN), luminal A (ER+) and HER2+ tumour types, were mapped on human protein interactome to construct targeted subnetworks. The subnetworks were analysed for enriched oncogenic signalling pathways. Pathway redundancy was reduced by constructing pathway-pathway interaction networks, and the sets of overlapping genes were subsequently used to infer pathway crosstalk. The resulting filtered pathways were mapped on oncogenesis processes to evaluate their anti-carcinogenic effectiveness, and thus putative mechanisms of action. Results The signalling pathways regulated by Actein, Withaferin A, Indole-3-Carbinol and Compound Kushen, which are extensively researched compounds, were shown to be projected on a set of oncogenesis processes at the transcriptomic level in different breast cancer subtypes. The enrichment of well-known tumour driving genes indicate that these compounds indirectly dysregulate cancer driving pathways in the subnetworks. Conclusion The proposed framework infers the mechanisms of action of potential drug candidates from their enriched protein interaction subnetworks and oncogenic signalling pathways. It also provides a systematic approach for evaluating such compounds in polygenic complex diseases. In addition, the plant-based compounds used here show poly-pharmacologic mechanism of action by targeting subnetworks enriched with cancer driving genes. This network perspective supports the need for a systemic drug-target evaluation for lead compounds prior to efficacy experiments.

Branchial effects of epinephrine in the seawater-adapted mullet. II. Na+ and Cl- extrusion

1975 ◽  
Vol 228 (2) ◽  
pp. 441-447 ◽  
Author(s):  
P Pic ◽  
N Mayer-Gostan ◽  
J Maetz
Keyword(s):  
Exchange Mechanism ◽  
Beta Blockade ◽  
Oral Ingestion ◽  
Extrusion Rate ◽  
Alpha Blockers ◽  
Adrenergic Response ◽  
Alpha Blockade ◽  
Sodium Extrusion ◽  
Leak Pathway ◽  
Rapid Transfer

Injection of epinephrine into Mugil capito adapted to seawater is followed by a 40-60% inhibition of the Na and Cl effluxes. Simultaneously the Na influx is decreased by 30%, the overall result being a reduction of the net sodium extrusion rate by the gill. The change in Na influx is in part explained by a 75-80% decrease of the oral ingestion of seawater. This branchial adrenergic response is sensitive to alpha-blockade by phentolamine and tolazoline and insensitive to beta-blockade by propranolol. Both alpha-blockers are ineffective when injected alone. Propranolol injected alone mimics epinephrine while simultaneous injection of phentolamine blocks the response to propranolol. Rapid transfer experiments suggest that epinephrine inhibits the branchial Cl pump and its associated Na/K exchange mechanism. The leak pathway for these ions remains insensitive to epinephrine.

scholarly journals Exaggerated cation leak from oxygenated sickle red blood cells during deformation: evidence for a unique leak pathway

Blood ◽  
1992 ◽  
Vol 80 (9) ◽  
pp. 2374-2378
Author(s):  
T Sugihara ◽  
RP Hebbel
Keyword(s):  
Shear Stress ◽  
Lipid Hydroperoxide ◽  
Viscous Medium ◽  
Permeability Barrier ◽  
Biochemical Basis ◽  
Rbc Membrane ◽  
Gardos Channel ◽  
Ambient Oxygen ◽  
Applied Shear Stress ◽  
Leak Pathway

An abnormal susceptibility of the sickle red blood cell (RBC) membrane to deformation could compromise its permeability barrier function and contribute to the exuberant cation leakiness occurring during the sickling phenomenon. We examined this hypothesis by subjecting RBCs at ambient oxygen tension to elliptical deformation, applying shear stress in a viscous medium under physiologic conditions. Compared with normal and high-reticulocyte control RBCs, sickle RBCs manifest an exaggerated K leak response to deformation. This leak is fully reversible, is both Cl and Ca independent, and at pHe 7.4 is fully balanced so that Kefflux equals Nainflux. This abnormal susceptibility is also evident in that the K leak in response to deformation occurs at an applied shear stress of only 141 dyne/cm2 for sickle RBCs, as compared to 204 dyne/cm2 for normal RBCs. Fresh sickle RBC membranes contain elevated amounts of lipid hydroperoxide, the presence of which is believed to provide the biochemical basis for enhanced deformation susceptibility. When examined at pHe 6.8, oxygenated sickle RBCs acquire an additional, unbalanced (Kefflux > Nainflux) component to the K leak increment specifically ascribable to deformation. Studies with inhibitors suggest that this additional component is not caused by a known leak pathway (eg, either K:Cl cotransport or the Gardos channel). This abnormal susceptibility of the sickle membrane to development of cation leakiness during deformation probably contributes to the exuberant cation leak taking place during RBC sickling.

scholarly journals Cytoskeletal Proteins in Cancer and Intracellular Stress: A Therapeutic Perspective

Cancers ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 238 ◽  
Author(s):  
Mei Shan Ong ◽  
Shuo Deng ◽  
Clarissa Esmeralda Halim ◽  
Wanpei Cai ◽  
Tuan Zea Tan ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Cytoskeletal Proteins ◽  
Cellular Processes ◽  
Oxidative Stresses ◽  
Cytoskeletal Responses ◽  
Therapeutic Perspective ◽  
Promote Tumour Development ◽  
Oncogenic Signalling

Cytoskeletal proteins, which consist of different sub-families of proteins including microtubules, actin and intermediate filaments, are essential for survival and cellular processes in both normal as well as cancer cells. However, in cancer cells, these mechanisms can be altered to promote tumour development and progression, whereby the functions of cytoskeletal proteins are co-opted to facilitate increased migrative and invasive capabilities, proliferation, as well as resistance to cellular and environmental stresses. Herein, we discuss the cytoskeletal responses to important intracellular stresses (such as mitochondrial, endoplasmic reticulum and oxidative stresses), and delineate the consequences of these responses, including effects on oncogenic signalling. In addition, we elaborate how the cytoskeleton and its associated molecules present themselves as therapeutic targets. The potential and limitations of targeting new classes of cytoskeletal proteins are also explored, in the context of developing novel strategies that impact cancer progression.

scholarly journals The accumulation of amino acids by mouse ascites-tumour cells. Dependence on but lack of equilibrium with the sodium-ion electrochemical gradient

1981 ◽  
Vol 194 (2) ◽  
pp. 415-426 ◽  
Author(s):  
C Hacking ◽  
A A Eddy
Keyword(s):  
Amino Acids ◽  
Steady State ◽  
Amino Acid ◽  
Rate Coefficient ◽  
Tumour Cells ◽  
Cellular Respiration ◽  
Mouse Ascites ◽  
Predicted Values ◽  
Leak Pathway ◽  
Ascites Tumour Cells

1. The fluorescent dye 3,3′-dipropyloxadicarbocyanine was used to show that the tumour cells absorbed 2-aminoisobutyrate, glycine, L-leucine and L-isoleucine and certain other amino acids electrogenically. The Km values with respect to amino acid concentration ([A]o), obtained from the fluorescence assays, varied through the above series from 0.8 to 26 mM, with Vmax. fairly constant. 2. Similar Km values described the uptake of the 14C-labelled amino acids in five instances where this was measured. 3. Each amino acid lowered the membrane potential (E) by 10-20 mV when its cellular concentration ([A]i) had reached a steady value and [A]o was 10mM. In these experiments energy metabolism was maintained by glycolysis, 2,4-dinitrophenol was present and cellular respiration was inhibited. The corresponding net flow of amino acid through the Na+ symport was deduced by making use of the fact that the depolarization an amino acid initially caused was roughly proportional to the net influx of amino acid itself. 4. The steady-state depolarization was attributed to the presence of a leak pathway for the amino acid with a rate coefficient PA. As assayed in the absence of Na+, PA was about 5-fold larger for isoleucine than for glycine. 5. Direct estimates of Vmax./PA were similar to those inferred from the extent of depolarization in the steady state and [A]i. 6. A mathematical model was used to predict [A]i/[A]o in term of the measured values of [Na]o, [Na]i, E, Km and Vmax./PA. The predicted and observed values agreed fairly well when [A]o was 1 mM or 10 mM. 7. [A]i/[A]o varied from about 2.5 for 10 mM-isoleucine to 30 for 1 mM-2-aminoisobutyrate when delta microNa, expressed as a ratio, was ostensibly in the range 19-43. 8. The concentration of 2-aminoisobutyrate from a 0.1 mM solution in the presence or absence of ouabain was consistent with the model, whereas the concentration of isoleucine from a 0.1 mM solution exceeded the predicted values 2-5-fold. 9. The tumour cells concentrated 2-amino-bicyclo[2,2,1]heptane-2-carboxylic acid by a non-electrogenic mechanism, with which isoleucine may also interact.

scholarly journals MicroRNA Regulation of Glycolytic Metabolism in Glioblastoma

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Huda Alfardus ◽  
Alan McIntyre ◽  
Stuart Smith
Keyword(s):  
Aerobic Glycolysis ◽  
Signalling Pathways ◽  
Glycolytic Metabolism ◽  
Malignant Brain Tumour ◽  
Coding Sequences ◽  
Microrna Regulation ◽  
Regulation Of Metabolism ◽  
Cancer Types ◽  
Mirnas Expression ◽  
Oncogenic Signalling

Glioblastoma (GBM) is the most aggressive and common malignant brain tumour in adults. A well-known hallmark of GMB and many other tumours is aerobic glycolysis. MicroRNAs (miRNAs) are a class of short nonprotein coding sequences that exert posttranscriptional controls on gene expression and represent critical regulators of aerobic glycolysis in GBM. In GBM, miRNAs regulate the expression of glycolytic genes directly and via the regulation of metabolism-associated tumour suppressors and oncogenic signalling pathways. This review aims to establish links between miRNAs expression levels, the expression of GBM glycolytic regulatory genes, and the malignant progression and prognosis of GBM. In this review, the involvement of 25 miRNAs in the regulation of glycolytic metabolism of GBM is discussed. Seven of these miRNAs have been shown to regulate glycolytic metabolism in other tumour types. Further eight miRNAs, which are differentially expressed in GBM, have also been reported to regulate glycolytic metabolism in other cancer types. Thus, these miRNAs could serve as potential glycolytic regulators in GBM but will require functional validation. As such, the characterisation of these molecular and metabolic signatures in GBM can facilitate a better understanding of the molecular pathogenesis of this disease.

scholarly journals Use of RNA interference libraries to investigate oncogenic signalling in mammalian cells

Oncogene ◽  
2004 ◽  
Vol 23 (51) ◽  
pp. 8376-8383 ◽  
Author(s):  
Julian Downward
Keyword(s):  
Rna Interference ◽  
Mammalian Cells ◽  
Oncogenic Signalling

scholarly journals Correlation of occludin protein mobility with paracellular leak pathway permeability in renal epithelia

2018 ◽  
Author(s):  
Josephine Axis ◽  
Alexander L. Kolb ◽  
Robert L. Bacallao ◽  
Kurt Amsler
Keyword(s):  
Tight Junction ◽  
Ischemia Reperfusion Injury ◽  
Mdck Cells ◽  
Ischemia Reperfusion ◽  
Paracellular Permeability ◽  
Tight Junction Protein ◽  
Protein Mobility ◽  
Junction Protein ◽  
Leak Pathway

ABSTRACTStudies have demonstrated regulation of the epithelial paracellular permeability barrier, the tight junction, by a variety of stimuli. Recent studies have reported a correlation between changes in paracellular permeability, particularly paracellular permeability to large solutes (leak pathway), and mobility of the tight junction protein, occludin, in the plane of the plasma membrane. This had led to the hypothesis that changes in occludin protein mobility are causative for changes in paracellular permeability. Using a renal epithelial cell model system, MDCK, we examined the effect of various manipulations on both leak pathway permeability, monitored as the paracellular movement of a fluorescent molecule (calcein), and occludin protein mobility, monitored through fluorescence recovery after photobleaching. Our results indicate that knockdown of the associated tight junction protein, ZO-1, increases baseline leak pathway permeability, whereas, knockdown of the related tight junction protein, ZO-2, does not alter baseline leak pathway permeability. Knockdown of either ZO-1 or ZO-2 decreases the rate of movement of occludin protein but only knockdown of ZO-2 protein alters the percent of occludin protein that is mobile. Further, treatment with hydrogen peroxide increases leak pathway permeability in wild type MDCK cells and in ZO-2 knockdown MDCK cells but not in ZO-1 knockdown MDCK cells. This treatment decreases the rate of occludin movement in all three cell lines but only alters the mobile fraction of occludin protein in ZO-1 knockdown MDCK cells. Finally, we examined the effect of renal ischemia/reperfusion injury on occludin protein mobility in vivo.Ischemia/reperfusion injury both increased the rate of occludin mobility and increased the fraction of occludin protein that is mobile. These results indicate that, at least in our cell culture and in vivo model systems, there is no consistent correlation between paracellular leak pathway permeability and occludin protein mobility.

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