Search results for "protein kinase"
showing 10 items of 1188 documents
The interleukin (IL)-31/IL-31R axis contributes to tumor growth in human follicular lymphoma
2014
Interleukin (IL)-31A binds to an heterodimer composed of IL-31 receptor A (IL-31RA) and Oncostatin M Receptor (OSMR). The IL-31/IL-31R complex is involved in the pathogenesis of various skin diseases, including cutaneous T-cell lymphoma. No information is available on the relations between the IL-31/IL-31R complex and B-cell lymphoma. Here we have addressed this issue in follicular lymphoma (FL), a prototypic germinal center(GC)-derived B-cell malignancy. IL-31 enhanced primary FL cell proliferation through IL-31R-driven signal transducer and activator of transcription factor 1/3 (STAT1/3), extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt phosphorylation. In contrast, GC B cells d…
The emergence of drug resistance to targeted cancer therapies: Clinical evidence.
2019
For many decades classical anti-tumor therapies included chemotherapy, radiation and surgery; however, in the last two decades, following the identification of the genomic drivers and main hallmarks of cancer, the introduction of therapies that target specific tumor-promoting oncogenic or non-oncogenic pathways, has revolutionized cancer therapeutics. Despite the significant progress in cancer therapy, clinical oncologists are often facing the primary impediment of anticancer drug resistance, as many cancer patients display either intrinsic chemoresistance from the very beginning of the therapy or after initial responses and upon repeated drug treatment cycles, acquired drug resistance deve…
Intratumoral Heterogeneity in EGFR-Mutant NSCLC Results in Divergent Resistance Mechanisms in Response to EGFR Tyrosine Kinase Inhibition
2015
Abstract Non–small cell lung cancers (NSCLC) that have developed resistance to EGF receptor (EGFR) tyrosine kinase inhibitor (TKI), including gefitinib and erlotinib, are clinically linked to an epithelial-to-mesenchymal transition (EMT) phenotype. Here, we examined whether modulating EMT maintains the responsiveness of EGFR-mutated NSCLCs to EGFR TKI therapy. Using human NSCLC cell lines harboring mutated EGFR and a transgenic mouse model of lung cancer driven by mutant EGFR (EGFR-Del19-T790M), we demonstrate that EGFR inhibition induces TGFβ secretion followed by SMAD pathway activation, an event that promotes EMT. Chronic exposure of EGFR-mutated NSCLC cells to TGFβ was sufficient to ind…
To the research of treatments for the typical calcific disease of old aortic valve in the omics era: Is the miR-195 a therapeutic signature via targe…
2020
Calcific aortic valve disease (CAVD) is the most frequent form of val-vular pathology [1,2], with high percentages of mortality and morbidityin Western populations, so much to be a very public health problem [2].Diverse millions of subjects are affected by CAVD and the major numberare old individuals (65- older), even if some have a younger age and aregenerally affected by congenital bicuspid aortic valve (BAV) disease[2,3]. CAVD in BAV individuals arises decades earlier respect to subjectswith the physiological tricuspid aortic valve [3]. Furthermore, it can leadto death if untreated with surgical aortic valve replacement or trans-catheter aortic valve implantation, its unique treatments […
Glycolytic phenotype and AMP kinase modify the pathologic response of tumor xenografts to VEGF neutralization.
2011
Abstract VEGF antagonists are now widely used cancer therapeutics, but predictive biomarkers of response or toxicity remain unavailable. In this study, we analyzed the effects of anti-VEGF therapy on tumor metabolism and therapeutic response by using an integrated set of imaging techniques, including bioluminescence metabolic imaging, 18-fluorodeoxyglucose positron emission tomography, and MRI imaging and spectroscopy. Our results revealed that anti-VEGF therapy caused a dramatic depletion of glucose and an exhaustion of ATP levels in tumors, although glucose uptake was maintained. These metabolic changes selectively accompanied the presence of large necrotic areas and partial tumor regress…
Retrograde neurotrophic signaling in rat retinal ganglion cells is transmitted via the ERK5 but not the ERK1/2 pathway.
2014
Purpose Neurotrophic deprivation is considered an important event in glaucomatous retinal ganglion cell (RGC) death. However, the mitogen-activated protein kinase (MAPK) pathway transmitting axonal neurotrophic signals in RGC has not been identified. We investigated the involvement of ERK5 and ERK1/2 in retrograde axonal neurotrophic signaling in rats. Methods Adult Sprague-Dawley rats were used. Retinal immunostaining for ERK5 and MEK5 was performed. Levels of total and phosphorylated ERK5 and ERK1/2 were analyzed in retinal lysate by quantitative Western blotting. The effects of age, brain-derived neurotrophic factor (BDNF) stimulation at RGC soma (intravitreal injection) or axon ending (…
Advances in Targeting Signal Transduction Pathways
2012
// James A. McCubrey 1 , Linda S. Steelman 1 , William H. Chappell 1 , Lin Sun 1,2 , Nicole M. Davis 1 , Stephen L. Abrams 1 , Richard A. Franklin 1 , Lucio Cocco 3 , Camilla Evangelisti 4 , Francesca Chiarini 4 , Alberto M. Martelli 3,4 , Massimo Libra 5 , Saverio Candido 5 , Giovanni Ligresti 5 , Grazia Malaponte 5 , Maria C. Mazzarino 5 , Paolo Fagone 5 , Marco Donia 5 , Ferdinando Nicoletti 5 , Jerry Polesel 6 , Renato Talamini 6 , Jorg Basecke 7 , Sanja Mijatovic 8 , Danijela Maksimovic-Ivanic 8 , Michele Milella 9 , Agostino Tafuri 10 , Joanna Dulinska-Litewka 11 , Piotr Laidler 11 , Antonio B. D’Assoro 12 , Lyudmyla Drobot 13 , Kazuo Umezawa 14 , Giuseppe Montalto 15 , Melchiorre Cer…
A bacterial metabolite, trimethylamine N-oxide, disrupts the hemostasis balance in human primary endothelial cells but no coagulopathy in mice
2019
: The gut microbial metabolite, trimethylamine N-oxide (TMAO), was previously reported to induce platelet hypersensitivity, which leads to thrombotic risk. However, the molecular mechanism underlying the effects of TMAO on endothelial cells (EC), which is the primary vessel wall contact with the lumen, remains unclear. Here, we investigated the impact of TMAO on procoagulant activity (PCA) in EC and mice, for a possible link between microbiota and coagulation. To test the PCA of TMAO in EC, we performed one-stage clotting assays and converted into PCA. Antitissue factor (TF) antibody was used to test the TF role in PCA. Quantitative PCR was performed to measure the TF, thrombomodulin, IL-6,…
CXCR7 Reactivates ERK Signaling to Promote Resistance to EGFR Kinase Inhibitors in NSCLC
2019
Abstract Although EGFR mutant–selective tyrosine kinase inhibitors (TKI) are clinically effective, acquired resistance can occur by reactivating ERK. We show using in vitro models of acquired EGFR TKI resistance with a mesenchymal phenotype that CXCR7, an atypical G protein-coupled receptor, activates the MAPK–ERK pathway via β-arrestin. Depletion of CXCR7 inhibited the MAPK pathway, significantly attenuated EGFR TKI resistance, and resulted in mesenchymal-to-epithelial transition. CXCR7 overexpression was essential in reactivation of ERK1/2 for the generation of EGFR TKI–resistant persister cells. Many patients with non–small cell lung cancer (NSCLC) harboring an EGFR kinase domain mutatio…
Modulation of the control of mutagenic metabolites derived from cyclophosphamide and ifosfamide by stimulation of protein kinase A
1990
The phosphorylation of the 2 major phenobarbital-inducible cytochrome P450 isoenzymes IIB1 and IIB2 was increased in intact hepatocytes by the action of the membrane-permeating cAMP derivative N6,O2'-dibutyryl-cAMP. Under these conditions cyclophosphamide and ifosfamide (which are known to be activated by cytochrome P450 IIB1) were investigated for mutagenicity in Salmonella typhimurium TA1535 and TA100 and for cytotoxicity in TA1535. Cyclophosphamide and ifosfamide were transformed to mutagenic and cytotoxic metabolites by the hepatocytes. The activation of both drugs to mutagens was markedly reduced after pretreatment of the hepatocytes with the membrane-permeating cAMP derivative N6,O2'-…