scholarly journals The importance of preexisting drug resistance due to overexpression of P-glycoprotein for the formation of resistance to bortezomib

2020 ◽  
Vol 7 (1) ◽  
pp. 23-31
Author(s):  
L. A. Laletina ◽  
N. I. Moiseeva ◽  
A. F. Karamysheva
Keyword(s):  
Signal Transduction ◽  
Drug Resistance ◽  
Signaling Pathways ◽  
Signal Transduction Pathway ◽  
Pten Protein ◽  
Development Of Resistance ◽  
P Glycoprotein ◽  
A Cell ◽  
Kinase Expression ◽  
Human Signal

Objective of the study. In our work we investigated the effect of pre-existing drug resistance by the mechanism of activation of ABC transporters – P-glycoprotein (Pgp) overexpression – on the development of resistance to the proteasome inhibitor bortezomib.Materials and methods. Cultures RPMI8226 and K562 / i-S9 (with Pgp overexpression) and their bortezomib-resistant sublines RPMI8226 / btz-6 and K562 / i-S9vlc were used as models. The methods used were MTT test, flow cytometry, Western blot and real-time polymerase chain reaction using the Human Signal Transduction Pathway Finder system.Results. The expression of the main PI3K-AKT and NF-κB signaling pathways did not change in RPMI8226 / btz-6 subline cells. However, AKT kinase expression was significantly increased and PTEN protein expression was reduced in K562 / i-S9vlc cells with Pgp-overexpression. Significant changes in gene expression (42 %) were found in RPMI8226 / btz-6 cells related to a number of main signaling pathways in the tumor cell, namely: activation of 3–4 genes in signaling pathways related to hypoxia, oxidative stress, PPAR and p53. The highest activation in these cells was found in the TGFβ signaling pathway. In resistant K562 / i-S9vlc cells, expression of only 5 genes (10 %) increased: Fas, HMOX1, CPT2, ICAM, and SOCS3. Three genes were also identified that changed in both resistant sublines: Fas, HMOX1 and CPT2. Further, we showed that in the RPMI8226 / btz-6 subline, along with changes in the expression of signal transduction genes, there is a large pool of CD138-negative cells, and in the K562 / i-S9vlc subline, the number of cells expressing CD34 increases and the number of CD13 decreases.Conclusion. We found that different signaling pathways are involved in the formation of resistance to bortezomib in the absence of Pgp expression and its overexpression. In addition, a cell line without activated resistance pathways requires more extensive rearrangements in the signal system to acquire resistance to bortezomib. However, in both cases, bortezomib leads to a change in the immunophenotype of the cells – to the appearance of dedifferentiated subpopulations.

scholarly journals Modulation of Bovine Endometrial Cell Receptors and Signaling Pathways as a Nanotherapeutic Exploration against Dairy Cow Postpartum Endometritis

Animals ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 1516
Author(s):  
Ayodele Olaolu Oladejo ◽  
Yajuan Li ◽  
Xiaohu Wu ◽  
Bereket Habte Imam ◽  
Jie Yang ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Signaling Pathways ◽  
Inflammatory Cytokines ◽  
Signal Transduction Pathway ◽  
Endometrial Cell ◽  
Cell Receptors ◽  
Endometrial Cells ◽  
Microbial Invasion ◽  
Pass Through ◽  
Pro Inflammatory Cytokines

In order to control and prevent bovine endometritis, there is a need to understand the molecular pathogenesis of the infectious disease. Bovine endometrium is usually invaded by a massive mobilization of microorganisms, especially bacteria, during postpartum dairy cows. Several reports have implicated the Gram-negative bacteria in the pathogenesis of bovine endometritis, with information dearth on the potentials of Gram-positive bacteria and their endotoxins. The invasive bacteria and their ligands pass through cellular receptors such as TLRs, NLRs, and biomolecular proteins of cells activate the specific receptors, which spontaneously stimulates cellular signaling pathways like MAPK, NF-kB and sequentially triggers upregulation of pro-inflammatory cytokines. The cascade of inflammatory induction involves a dual signaling pathway; the transcription factor NF-κB is released from its inhibitory molecule and can bind to various inflammatory genes promoter. The MAPK pathways are concomitantly activated, leading to specific phosphorylation of the NF-κB. The provision of detailed information on the molecular pathomechanism of bovine endometritis with the interaction between host endometrial cells and invasive bacteria in this review would widen the gap of exploring the potential of receptors and signal transduction pathways in nanotechnology-based drug delivery system. The nanotherapeutic discovery of endometrial cell receptors, signal transduction pathway, and cell biomolecules inhibitors could be developed for strategic inhibition of infectious signals at the various cell receptors and signal transduction levels, interfering on transcription factors activation and pro-inflammatory cytokines and genes expression, which may significantly protect endometrium against postpartum microbial invasion.

scholarly journals Ala/Thr201 in Extracellular Loop 2 and Leu/Phe290 in Transmembrane Domain 6 of Type 1 Frog Gonadotropin-Releasing Hormone Receptor Confer Differential Ligand Sensitivity and Signal Transduction

Endocrinology ◽  
2003 ◽  
Vol 144 (2) ◽  
pp. 454-466 ◽  
Author(s):  
Jae Young Seong ◽  
Li Wang ◽  
Da Young Oh ◽  
Oim Yun ◽  
Kaushik Maiti ◽  
...  
Keyword(s):  
Gene Expression ◽  
Signal Transduction ◽  
Signaling Pathways ◽  
Transmembrane Domain ◽  
Inositol Phosphate ◽  
Signal Transduction Pathway ◽  
Extracellular Loop ◽  
Loop 2 ◽  
Ligand Sensitivity

Recently, we have identified three distinct types of bullfrog GnRH receptor (designated bfGnRHR-1, bfGnRHR-2, and bfGnRHR-3). In the present study, we have isolated three GnRHR clones in Rana dybowskii (dyGnRHR-1, dyGnRHR-2, and dyGnRHR-3). Despite high homology of dyGnRHRs with the corresponding bfGnRHRs, dyGnRHRs revealed different signaling pathways and ligand sensitivity compared with the bfGnRHR counterparts. Activation of dyGnRHRs with GnRH stimulated cAMP-mediated gene expression. However, dyGnRHR-3 but not dyGnRHR-1 and -2 induced c-fos promoter-driven gene expression. Consistently, dyGnRHR-1 and dyGnRHR-2 were not able to increase GnRH-induced inositol phosphate accumulation, whereas all bfGnRHRs and dyGnRHR-3 were, indicating that dyGnRHR-1 and dyGnRHR-2 are coupled to solely Gs, whereas all bfGnRHRs and dyGnRHR-3 are coupled to both Gs and Gq/11. Moreover, dyGnRHR-1 and dyGnRHR-2 showed about 10-fold less sensitivity to each ligand than that of the bfGnRHR counterparts. Using type 1 chimeric and point-mutated receptors, we further elucidated that specific amino acids, Ala/Thr201 in extracellular loop 2 and Leu/Phe290 in transmembrane domain 6 of the type 1 receptor, are responsible for ligand sensitivity and signal transduction pathway. Particularly, substitution of Leu290 to Phe in dyGnRHR-1 increased GnRH-induced inositol phosphate production as well as c-fos promoter-driven gene expression whereas substitution of Phe290 to Leu in bfGnRHR-1 decreased those activities. Collectively, these results demonstrate the presence of three types of GnRHR in amphibians, and suggest species- and type-specific ligand recognition and different signaling pathways in frog GnRHRs.

scholarly journals Exposure of Cells to a Cell Number-Counting Factor Decreases the Activity of Glucose-6-Phosphatase To Decrease Intracellular Glucose Levels in Dictyostelium discoideum

2005 ◽  
Vol 4 (1) ◽  
pp. 72-81 ◽  
Author(s):  
Wonhee Jang ◽  
Richard H. Gomer
Keyword(s):  
Signal Transduction ◽  
Dictyostelium Discoideum ◽  
Group Size ◽  
Signal Transduction Pathway ◽  
Glucose Production ◽  
Cell Number ◽  
Glucose Levels ◽  
A Cell ◽  
Induced Changes ◽  
Intracellular Glucose

ABSTRACT The development of Dictyostelium discoideum is a model for tissue size regulation, as these cells form groups of ≈2 × 104 cells. The group size is regulated in part by a negative feedback pathway mediated by a secreted multipolypeptide complex called counting factor (CF). CF signal transduction involves decreasing intracellular CF glucose levels. A component of CF, countin, has the bioactivity of the entire CF complex, and an 8-min exposure of cells to recombinant countin decreases intracellular glucose levels. To understand how CF regulates intracellular glucose, we examined the effect of CF on enzymes involved in glucose metabolism. Exposure of cells to CF has little effect on amylase or glycogen phosphorylase, enzymes involved in glucose production from glycogen. Glucokinase activity (the first specific step of glycolysis) is inhibited by high levels of CF but is not affected by an 8-min exposure to countin. The second enzyme specific for glycolysis, phosphofructokinase, is not regulated by CF. There are two corresponding enzymes in the gluconeogenesis pathway, fructose-1,6-bisphosphatase and glucose-6-phosphatase. The first is not regulated by CF or countin, whereas glucose-6-phosphatase is regulated by both CF and an 8-min exposure to countin. The countin-induced changes in the Km and V max of glucose-6-phosphatase cause a decrease in glucose production that can account for the countin-induced decrease in intracellular glucose levels. It thus appears that part of the CF signal transduction pathway involves inhibiting the activity of glucose-6-phosphatase, decreasing intracellular glucose levels and affecting the levels of other metabolites, to regulate group size.

scholarly journals Potential role of transforming growth factor beta1 in drug resistance of tumor cells.

2003 ◽  
Vol 50 (2) ◽  
pp. 497-508 ◽  
Author(s):  
Rostyslav Stoika ◽  
Mariya Yakymovych ◽  
Serhiy Souchelnytskyi ◽  
Ihor Yakymovych
Keyword(s):  
Signal Transduction ◽  
Drug Resistance ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Signal Transduction Pathway ◽  
Target Cells ◽  
Type I ◽  
Transduction Pathway ◽  
L1210 Cells ◽  
Anti Cancer

Acquired drug resistance of tumor cells is frequently observed in cancer patients undergoing chemotherapy. We studied murine leukemia L1210 cells sensitive and resistant to the cytotoxic action of cisplatin and showed that cisplatin-resistant leukemia cells were also refractory to TGF beta1-dependent growth inhibition and apoptosis. Addressing the question about the mechanisms responsible for the cross-resistance to cisplatin and TGF beta1, we found that cisplatin- and TGF beta1-resistant L1210 cells possessed a decreased expression of type I TGF beta1 receptor, while the expression of type II TGF beta1 receptor was not affected. Western blot analysis of Smad proteins 2, 3, 4, 6, and 7, which participate in signal transduction pathway down-stream of the TGF beta1 receptors, revealed an increased expression of Smad 6, inhibiting TGF beta1 action, only in cisplatin- and TGF beta1-resistant L1210 cells. TGF beta1 and especially the cytotoxic mistletoe agglutinin increased Smad 6 expression in TGF beta1-sensitive but not in TGF beta1-resistant L1210 cells. TGF beta1-resistant L1210 cells also differed from TGF beta1-sensitive cells by the lack of expression of the pro-apoptotic p53 protein and higher level of expression of the anti-apoptotic Bcl-2 protein. Thus, the described co-expression of tumor cell refractoriness to an anti-cancer drug and to the inhibitory cytokine TGF beta1 is accompanied by multiple changes in the TGF beta1 signal transduction pathway and in other regulatory systems of the target cells. Besides, we found that various anti-tumor drugs and cytotoxic plant lectins increased the level of TGF beta1 expression in both TGFbeta1-sensitive and -resistant L1210 cells. A hypothesis is proposed that TGFbeta1 can at least partly mediate the effect of cell-stressing agents and, thus, the development of TGF beta1 resistance may be responsible for the appearance of tumor cell refractoriness to the action of some anti-cancer drugs.

CD40/CD154 ligation induces mononuclear cell adhesion to human renal proximal tubule cells via increased ICAM-1 expression

2005 ◽  
Vol 289 (1) ◽  
pp. F145-F153 ◽  
Author(s):  
Hongye Li ◽  
Edward P. Nord
Keyword(s):  
Signal Transduction ◽  
Cell Adhesion ◽  
Proximal Tubule ◽  
Mononuclear Cell ◽  
Mononuclear Cells ◽  
Gene Array ◽  
Signal Transduction Pathway ◽  
Renal Proximal Tubule ◽  
Transduction Pathway ◽  
A Cell

The role of CD40/CD154 ligation in the upregulation of genes of the proinflammatory nuclear factor-κB (NF-κB) signal transduction pathway was explored in primary cultures of human renal proximal tubule epithelial cells. Using a cDNA gene array specific for human NF-κB signal pathway genes, 38 genes were upregulated at 1 h, and 7 of these genes remained upregulated at 3 h. Of these genes, intercellular adhesion molecule-1 (ICAM-1) was explored in further detail. Quantitative real-time PCR for ICAM-1 mRNA expression confirmed the gene array findings. Western blot analysis and quantitative sandwich-enzyme ELISA confirmed this observation at the protein level. A cell-surface ELISA assay showed that ICAM-1 expression doubled by 48 h of CD154 exposure, and fluorescence-activated cell sorter analysis suggested that both the number of cells expressing ICAM-1 and the expression of ICAM-1 on these cells had increased. A cell adhesion assay using fluorescein-labeled human peripheral mononuclear cells showed that ICAM-1 upregulation resulted in increased mononuclear cell adhesion to the monolayer, which was abrogated by pretreatment of the monolayer with a neutralizing ICAM-1 antibody. The p38 mitogen-activated protein kinase (MAPK) inhibitor SB-203580 but not the extracellular signal-regulated kinase 1/2 inhibitor (PD-98059) nor the protein kinase C inhibitor (calphostin) blunted ICAM-1 expression and mononuclear cell adhesion to the monolayer. We conclude that, in human renal proximal tubule epithelial cells, CD40 activation upregulates ICAM-1 (and other NF-κB pathway genes) expression with concomitant enhanced adhesion of mononuclear cells, which is mediated via the p38 MAPK signal transduction pathway.

scholarly journals Wnt/β-catenin signal transduction pathway in prostate cancer and associated drug resistance

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Chunyang Wang ◽  
Qi Chen ◽  
Huachao Xu
Keyword(s):  
Prostate Cancer ◽  
Signal Transduction ◽  
Drug Resistance ◽  
Androgen Receptor ◽  
Signal Transduction Pathway ◽  
Transduction Pathway ◽  
Cancer Pathogenesis ◽  
Asian Men ◽  
Therapy Development ◽  
The Impact

AbstractGlobally, prostate cancer ranks second in cancer burden of the men. It occurs more frequently in black men compared to white or Asian men. Usually, high rates exist for men aged 60 and above. In this review, we focus on the Wnt/β-catenin signal transduction pathway in prostate cancer since many studies have reported that β-catenin can function as an oncogene and is important in Wnt signaling. We also relate its expression to the androgen receptor and MMP-7 protein, both critical to prostate cancer pathogenesis. Some mutations in the androgen receptor also impact the androgen-β-catenin axis and hence, lead to the progression of prostate cancer. We have also reviewed MiRNAs that modulate this pathway in prostate cancer. Finally, we have summarized the impact of Wnt/β-catenin pathway proteins in the drug resistance of prostate cancer as it is a challenging facet of therapy development due to the complexity of signaling pathways interaction and cross-talk.

scholarly journals The negative regulator of Gli, Suppressor of fused (Sufu), interacts with SAP18, Galectin3 and other nuclear proteins

2004 ◽  
Vol 378 (2) ◽  
pp. 353-362 ◽  
Author(s):  
Mélanie PACES-FESSY ◽  
Dominique BOUCHER ◽  
Emile PETIT ◽  
Sandrine PAUTE-BRIAND ◽  
Marie-Françoise BLANCHET-TOURNIER
Keyword(s):  
Signal Transduction ◽  
Nuclear Export ◽  
Nuclear Export Signal ◽  
Signal Transduction Pathway ◽  
Biochemical Properties ◽  
Negative Regulator ◽  
Nuclear Proteins ◽  
Suppressor Of Fused ◽  
Activation Of Transcription ◽  
A Cell

Sufu (Suppressor of fused) is a negative regulator of the Hedgehog signal-transduction pathway, interacting directly with the Gli family of transcription factors. However, its function remains poorly understood. In the present study, we determined the expression, tissue distribution and biochemical properties of mSufu (mouse Sufu) protein. We identified several mSufu variants of which some were phosphorylated. A yeast two-hybrid screen with mSufu as bait allowed us to identify several nuclear proteins as potential partners of mSufu. Most of these partners, such as SAP18 (Sin3-associated polypeptide 18), pCIP (p300/CBP-cointegrator protein) and PIAS1 (protein inhibitor of activated signal transduction and activators of transcription 1), are involved in either repression or activation of transcription and two of them, Galectin3 and hnRNPA1 (heterogeneous nuclear ribonucleoprotein A1), have a nuclear function in pre-mRNA splicing. We confirmed the mSufu–SAP18 and mSufu–Galectin3 interactions by independent biochemical assays. Using a cell transfection assay, we also demonstrated that mSufu protein (484 amino acids) is predominantly cytoplasmic but becomes mostly nuclear when a putative nuclear export signal is mutated or after treatment of the cells with leptomycin B. Moreover, mSufu is translocated to the nucleus when co-expressed with SAP18, which is normally found in this compartment. In contrast, Galectin3 is translocated to the cytoplasm when it is co-expressed with mSufu. Our findings indicate that mSufu is a shuttle protein that appears to be extremely versatile in its ability to bind different proteins in both the cytoplasm and nucleus.

scholarly journals An endogenous chemorepellent directs cell movement by inhibiting pseudopods at one side of cells

2019 ◽  
Vol 30 (2) ◽  
pp. 242-255 ◽  
Author(s):  
Ramesh Rijal ◽  
Kristen M. Consalvo ◽  
Christopher K. Lindsey ◽  
Richard H. Gomer
Keyword(s):  
Signal Transduction ◽  
Actin Polymerization ◽  
Formation Rate ◽  
Cell Movement ◽  
Signal Transduction Pathway ◽  
Pi3 Kinase ◽  
Signal Transduction Pathways ◽  
Ras Protein ◽  
A Cell ◽  
G Protein Coupled

Eukaryotic chemoattraction signal transduction pathways, such as those used by Dictyostelium discoideum to move toward cAMP, use a G protein–coupled receptor to activate multiple conserved pathways such as PI3 kinase/Akt/PKB to induce actin polymerization and pseudopod formation at the front of a cell, and PTEN to localize myosin II to the rear of a cell. Relatively little is known about chemorepulsion. We previously found that AprA is a chemorepellent protein secreted by Dictyostelium cells. Here we used 29 cell lines with disruptions of cAMP and/or AprA signal transduction pathway components, and delineated the AprA chemorepulsion pathway. We find that AprA uses a subset of chemoattraction signal transduction pathways including Ras, protein kinase A, target of rapamycin (TOR), phospholipase A, and ERK1, but does not require the PI3 kinase/Akt/PKB and guanylyl cyclase pathways to induce chemorepulsion. Possibly as a result of not using the PI3 kinase/Akt/PKB pathway and guanylyl cyclases, AprA does not induce actin polymerization or increase the pseudopod formation rate, but rather appears to inhibit pseudopod formation at the side of cells closest to the source of AprA.

Phospholipid(s) Associations in Cellular Structures

1997 ◽  
Author(s):  
Donald J. Hanahan
Keyword(s):  
Signal Transduction ◽  
Signal Transduction Pathway ◽  
Human Platelets ◽  
Biologically Active ◽  
Membrane Phospholipids ◽  
Stimulus Response ◽  
Cellular Events ◽  
Close Relationship ◽  
A Cell ◽  
In Cells

In the preceding chapter, the intent was to provide the reader with a broad perspective on the chemical characteristics of cellular phospholipids. At the same time, emphasis was placed on the potential usefulness of this information in dissecting the importance of phospholipids in cellular events, such as signal transduction. There is no doubt that the large number of observations reported on the close relationship of phospholipids to the transduction process has stimulated a widespread (and gratifying) interest in these compounds. Certainly it is very clear now that stimulus-induced activation of cells leads to the turnover of specific membrane phospholipids. The following diagram reemphasizes several, but not all, possible reaction pathways that can be invoked during an agonist (stimulus)–induced activation of a cell and gives the possible sequelae: In each of the above reactions, the substrates phosphatidylcholine and phosphatidylinositol bisphosphate normally are considered biologically inactive in membranes. Then, subsequent to activation of cellular phospholipases by a stimulus, biologically active products are formed from these compounds. Thus, inositol bisphosphate triggers the release of calcium ions from intracellular stores, diacylglycerol is implicated in the translocation and activation of protein kinase C, arachidonic acid can be converted to biologically active prostaglandins, and phosphatidic acid can be an agonist in its own right. The major point to be stressed here is that phospholipid turnover is intimately associated with the signal transduction pathway in cells. Hence an understanding of the chemistry of these phospholipids is of major relevance to delineating the complicated process of signal transduction. While investigation of the behavior of phospholipids in this pathway in platelets has been a consuming interest of this author, the main thrust in this book will be simply to acquaint the reader with the chemistry of phospholipids of major importance in signal transduction and also to discuss other phospholipids found in mammalian membranes. Inasmuch as most investigations on stimulus response in cells utilize quite small numbers of cells—for example, a typical experiment on human platelets might use 1 x 109 cells, which would yield ∼50 μg of total lipid—this poses a challenge to an investigator to be able to isolate and identify these lipids.

Cell polarity and locomotion, as well as endocytosis, depend on NSF

Development ◽  
2002 ◽  
Vol 129 (18) ◽  
pp. 4185-4192 ◽  
Author(s):  
Chris R. L. Thompson ◽  
Mark S. Bretscher
Keyword(s):  
Signal Transduction ◽  
Cell Polarity ◽  
Surface Membrane ◽  
Signal Transduction Pathway ◽  
Temperature Sensitive ◽  
Membrane Recycling ◽  
Transduction Pathway ◽  
Tentative Model ◽  
Sensitive Factor ◽  
A Cell

NEM-sensitive factor (NSF) is an essential protein required during membrane transport. We replaced part of the endogenous D. discoideum NSF gene (nsfA) by a PCR-mutagenised library and isolated 11 mutants temperature-sensitive (ts) for growth. Two of these have been studied in detail. As expected, both are ts for FITC-dextran uptake by macropinocytosis, for internalising their surface membrane (monitored with FM1-43) and for phagocytosis. However, after 10-20 minutes at 28°C, they round up and cease to chemotax, move or cap ConA receptors. They fully recover when returned to 22°C. These cells carry out a normal ‘cringe’ reaction in response to cAMP, indicating that the actin cytoskeleton and this signal transduction pathway are still functional at 28°C. The behaviour of these mutants shows that NSF-catalysed processes are required not only for the different endocytic cycles but also for the maintenance of cell polarity. As cell locomotion depends on a cell having a polarity, the mutants stop moving at high temperature. A tentative model is proposed to explain the surprising link between membrane recycling and cell polarity revealed here.

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