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https://www.readbyqxmd.com/read/28438789/desmoglein-2-modulates-extracellular-vesicle-release-from-squamous-cell-carcinoma-keratinocytes
#1
Andrew M Overmiller, Jennifer A Pierluissi, Peter J Wermuth, Sami Sauma, Ubaldo Martinez-Outschoorn, Madalina Tuluc, Adam Luginbuhl, Joseph Curry, Larry A Harshyne, James K Wahl, Andrew P South, Mỹ G Mahoney
Extracellular vesicles (EVs) are nanoscale membrane-derived vesicles that serve as intercellular messengers carrying lipids, proteins, and genetic material. Substantial evidence has shown that cancer-derived EVs, secreted by tumor cells into the blood and other bodily fluids, play a critical role in modulating the tumor microenvironment and affecting the pathogenesis of cancer. Here we demonstrate for the first time that squamous cell carcinoma (SCC) EVs were enriched with the C-terminal fragment of desmoglein 2 (Dsg2), a desmosomal cadherin often overexpressed in malignancies...
April 24, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28427224/ponatinib-promotes-a-g1-cell-cycle-arrest-of-merlin-nf2-deficient-human-schwann-cells
#2
Alejandra M Petrilli, Jeanine Garcia, Marga Bott, Stephani Klingeman Plati, Christine T Dinh, Olena R Bracho, Denise Yan, Bing Zou, Rahul Mittal, Fred F Telischi, Xue-Zhong Liu, Long-Sheng Chang, D Bradley Welling, Alicja J Copik, Cristina Fernández-Valle
Neurofibromatosis type 2 (NF2) is a genetic syndrome that predisposes individuals to multiple benign tumors of the central and peripheral nervous systems, including vestibular schwannomas. Currently, there are no FDA approved drug therapies for NF2. Loss of function of merlin encoded by the NF2 tumor suppressor gene leads to activation of multiple mitogenic signaling cascades, including platelet-derived growth factor receptor (PDGFR) and SRC in Schwann cells. The goal of this study was to determine whether ponatinib, an FDA-approved ABL/SRC inhibitor, reduced proliferation and/or survival of merlin-deficient human Schwann cells (HSC)...
March 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/28426203/tyrosine-kinase-activation-and-conformational-flexibility-lessons-from-src-family-tyrosine-kinases
#3
Yilin Meng, Matthew P Pond, Benoît Roux
Protein kinases are enzymes that catalyze the covalent transfer of the γ-phosphate of an adenosine triphosphate (ATP) molecule onto a tyrosine, serine, threonine, or histidine residue in the substrate and thus send a chemical signal to networks of downstream proteins. They are important cellular signaling enzymes that regulate cell growth, proliferation, metabolism, differentiation, and migration. Unregulated protein kinase activity is often associated with a wide range of diseases, therefore making protein kinases major therapeutic targets...
April 20, 2017: Accounts of Chemical Research
https://www.readbyqxmd.com/read/28419476/cortactin-a-lyn-substrate-is-a-checkpoint-molecule-at-the-intersection-of-bcr-and-cxcr4-signalling-pathway-in-chronic-lymphocytic-leukaemia-cells
#4
Veronica Martini, Cristina Gattazzo, Federica Frezzato, Valentina Trimarco, Marco Pizzi, Giorgia Chiodin, Filippo Severin, Edoardo Scomazzon, Vincenza Guzzardo, Deborah Saraggi, Flavia Raggi, Leonardo Martinello, Monica Facco, Andrea Visentin, Francesco Piazza, Anna Maria Brunati, Gianpietro Semenzato, Livio Trentin
Cortactin (CTTN) is a substrate of the Src kinase Lyn that is known to play an actin cytoskeletal regulatory role involved in cell migration and cancer progression following its phosphorylation at Y421. We recently demonstrated that Cortactin is overexpressed in patients with chronic lymphocytic leukaemia (CLL). This work was aimed at defining the functional role of Cortactin in these patients. We found that Cortactin is variably expressed in CLL patients both in the peripheral blood and lymph nodes and that its expression correlates with the release of matrix metalloproteinase 9 (MMP-9) and the motility of neoplastic cells...
April 17, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28416483/sfk-fak-signaling-attenuates-osimertinib-efficacy-in-both-drug-sensitive-and-drug-resistant-models-of-egfr-mutant-lung-cancer
#5
Eiki Ichihara, David Westover, Catherine B Meador, Yingjun Yan, Joshua A Bauer, Pengcheng Lu, Fei Ye, Amanda Kulick, Elisa De Stanchina, Robert McEwen, Marc Ladanyi, Darren Cross, William Pao, Christine M Lovly
Mutant-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), such as osimertinib, are active agents for the treatment of EGFR-mutant lung cancer. Specifically, these agents can overcome the effects of the T790M mutation, which mediates resistance to first and second-generation EGFR TKI, and recent clinical trials have documented their efficacy in patients with EGFR-mutant lung cancer. Despite promising results, therapeutic efficacy is limited by development of acquired resistance...
April 17, 2017: Cancer Research
https://www.readbyqxmd.com/read/28415724/pharmacological-inhibition-of-src-kinase-protects-against-acute-kidney-injury-in-a-murine-model-of-renal-ischemia-reperfusion
#6
Chongxiang Xiong, Xiujuan Zang, Xiaoxu Zhou, Lirong Liu, Monica V Masucci, Jinhua Tang, Xuezhu Li, Na Liu, George Bayliss, Ting C Zhao, Shougang Zhuang
Activation of Src kinase has been implicated in the pathogenesis of acute brain, liver, and lung injury. However, the role of Src in acute kidney injury (AKI) remains unestablished. To address this, we evaluated the effects of Src inhibition on renal dysfunction and pathological changes in a murine model of AKI induced by ischemia/reperfusion (I/R). I/R injury to the kidney resulted in increased Src phosphorylation at tyrosine 416 (activation). Administration of PP1, a highly selective Src inhibitor, blocked Src phosphorylation, improved renal function and ameliorated renal pathological damage...
March 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/28399921/s100%C3%AE-as-a-serum-marker-in-endocrine-resistant-breast-cancer
#7
Sara Charmsaz, Éamon Hughes, Fiona T Bane, Paul Tibbitts, Marie McIlroy, Christopher Byrne, Sinéad Cocchiglia, Jean McBryan, Bryan T Hennessy, Róisín M Dwyer, Michael J Kerin, Arnold D Hill, Leonie S Young
BACKGROUND: Endocrine therapy is standard treatment for estrogen receptor (ER)-positive breast cancer. However, its efficacy is limited by intrinsic and acquired resistance. Here the potential of S100β as a biomarker and inhibition of its signaling network as a therapeutic strategy in endocrine treated patients was investigated. METHODS: The expression of S100β in tissue and serum was assessed by immunohistochemistry and an enzyme-linked immunosorbent assay, respectively...
April 12, 2017: BMC Medicine
https://www.readbyqxmd.com/read/28397850/interaction-of-src-and-alpha-v-integrin-regulates-fibroblast-migration-and-modulates-lung-fibrosis-in-a-preclinical-model-of-lung-fibrosis
#8
Yin-Ying Lu, Xue-Ke Zhao, Lei Yu, Fei Qi, Bing Zhai, Chang-Qing Gao, Qiang Ding
Src kinase is known to regulate fibroblast migration. However, the contribution of integrin and Src kinase interaction to lung fibrosis has not been mechanistically investigated. Our data demonstrate that integrin alpha v (αV) recruited Src kinase and that leads to subsequent Src activation in fibroblasts plated on fibrotic matrix, osteopontin. Src interaction with integrin αV is required for integrin αV-mediated Src activation, and the subsequent fibroblast migration. The study identified that β5 and β3 are the major integrins for this effect on osteopontin...
April 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28396358/extracellular-matrix-integrin-signaling-promotes-resistance-to-combined-inhibition-of-her2-and-pi3k-in-her2-breast-cancer
#9
Ariella B Hanker, Monica Valeria Estrada, Giampaolo Bianchini, Preston D Moore, Junfei Zhao, Feixiong Cheng, Luca Gianni, James P Koch, Darren R Tyson, Violeta Sanchez, Brent N Rexer, Melinda Sanders, Zhongming Zhao, Thomas Stricker, Carlos L Arteaga
PIK3CA mutations are associated with resistance to HER2-targeted therapies. We previously showed that HER2+/PIK3CA(H1047R) transgenic mammary tumors are resistant to the HER2 antibodies trastuzumab and pertuzumab but respond to PI3K inhibitor buparlisib (TPB). In this study, we identified mechanisms of resistance to combined inhibition of HER2 and PI3K. TPB-resistant tumors were generated by treating HER2+/PIK3CA(H1047R) mice long-term with the drug combination. RNA-sequencing of TPB-resistant tumors revealed that extracellular matrix (ECM) and cell adhesion genes, including collagen II (Col2a1), were markedly upregulated, accompanied by activation of integrin β1/Src...
April 10, 2017: Cancer Research
https://www.readbyqxmd.com/read/28393886/ve-cadherin-disassembly-and-cell-contractility-in-the-endothelium-are-necessary-for-barrier-disruption-induced-by-tumor-cells
#10
Virginia Aragon-Sanabria, Steven E Pohler, Vikram J Eswar, Matthew Bierowski, Esther W Gomez, Cheng Dong
During metastasis, breakdown of the endothelial barrier is critical for tumor cell extravasation through blood vessel walls and is mediated by a combination of tumor secreted soluble factors and receptor-ligand interactions. However, a complete mechanism governing tumor cell transendothelial migration remains unclear. Here, we investigate the roles of tumor-associated signals in regulating endothelial cell contractility and adherens junction disassembly leading to endothelial barrier breakdown. We show that Src mediates VE-cadherin disassembly in response to metastatic melanoma cells...
April 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28390937/steroid-receptor-coactivators-present-a-unique-opportunity-for-drug-development-in-hormone-dependent-cancers
#11
REVIEW
Aarti D Rohira, David M Lonard
Steroid receptor coactivators (SRCs) are essential regulators of nuclear hormone receptor function. SRCs coactivate transcription mediated by hormone stimulation of nuclear receptors and other transcription factors and have essential functions in human physiology and health. The SRCs are over expressed in a number of cancers such as breast, prostate, endometrial and pancreatic cancers where they promote tumor growth, invasion, metastasis and chemo-resistance. With their multiple roles in cancer, the SRCs are promising targets for the development of small molecule agents that can interfere with their function...
April 5, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28387310/targeting-bmk1-impairs-the-drug-resistance-to-combined-inhibition-of-braf-and-mek1-2-in-melanoma
#12
Chengli Song, Lina Wang, Qiang Xu, Kai Wang, Dan Xie, Zhe Yu, Kui Jiang, Lujian Liao, John R Yates, Jiing-Dwan Lee, Qingkai Yang
Combined inhibition of BRAF and MEK1/2 (CIBM) improves therapeutic efficacy of BRAF-mutant melanoma. However, drug resistance to CIBM is inevitable and the drug resistance mechanisms still remain to be elucidated. Here, we show that BMK1 pathway contributes to the drug resistance to CIBM. Considering that ERK1/2 pathway regulates cellular processes by phosphorylating, we first performed a SILAC phosphoproteomic profiling of CIBM. Phosphorylation of 239 proteins was identified to be downregulated, while phosphorylation of 47 proteins was upregulated...
April 7, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28387147/tyrosine-kinase-inhibitors-potential-use-and-safety-considerations-in-hiv-1-infection
#13
Mayte Coiras, Juan Ambrosioni, Francisco Cervantes, José M Miró, José Alcamí
Infection caused by HIV-1 is nowadays a chronic disease due to a highly efficient antiretroviral treatment that is nevertheless, unable to eliminate the virus from the organism. New strategies are necessary in order to impede the formation of the viral reservoirs, responsible for the failure of the antiretroviral treatment to cure the infection. Areas covered: The purpose of this review is to discuss the possibility of using tyrosine kinase inhibitors (TKIs) for the treatment of HIV-1 infection. These inhibitors are successfully used in patients with distinct cancers such as chronic myeloid leukemia...
April 7, 2017: Expert Opinion on Drug Safety
https://www.readbyqxmd.com/read/28385810/regulation-of-p53-mediated-changes-in-the-upa-fibrinolytic-system-and-in-lung-injury-by-loss-of-surfactant-protein-c-expression-in-alveolar-epithelial-cells
#14
Bijesh Puthusseri, Amarnath S Marudamuthu, Nivedita Tiwari, Jian Fu, Steven Idell, Sreerama Shetty
Pulmonary surfactant protein-C (SP-C) expression by type II alveolar epithelial cells (AECs) is markedly reduced in diverse types of lung injuries and is often associated with AEC apoptosis. It is unclear whether loss of SP-C contributes to the increased p53 and urokinase-type plasminogen activator (uPA) system cross talk and apoptosis of AECs. We therefore inhibited SP-C expression in human and murine AECs using lentivirus vector expressing shRNA and tested p53 and downstream changes in uPA-fibrinolytic system...
April 6, 2017: American Journal of Physiology. Lung Cellular and Molecular Physiology
https://www.readbyqxmd.com/read/28376152/co-activation-of-stat3-and-yes-associated-protein-1-yap1-pathway-in-egfr-mutant-nsclc
#15
Imane Chaib, Niki Karachaliou, Sara Pilotto, Jordi Codony Servat, Xueting Cai, Xuefei Li, Ana Drozdowskyj, Carles Codony Servat, Jie Yang, Chunping Hu, Andres Felipe Cardona, Guillermo Lopez Vivanco, Alain Vergnenegre, Jose Miguel Sanchez, Mariano Provencio, Noemi Reguart, Caicun Zhou, Peng Cao, Patrick C Ma, Trever G Bivona, Rafael Rosell
Background: The efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC) is limited by adaptive activation of cell survival signals. We hypothesized that both signal transducer and activator of transcription 3 (STAT3) and Src-YES-associated protein 1 (YAP1) signaling are dually activated during EGFR TKI treatment to limit therapeutic response. Methods: We used MTT and clonogenic assays, immunoblotting, and quantitative polymerase chain reaction to evaluate the efficacy of EGFR TKI alone and in combination with STAT3 and Src inhibition in three EGFR-mutant NSCLC cell lines...
September 1, 2017: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/28371355/bosutinib-an-src-inhibitor-induces-caspase-independent-cell-death-associated-with-permeabilization-of-lysosomal-membranes-in-melanoma-cells
#16
S Noguchi, S Shibutani, K Fukushima, T Mori, M Igase, T Mizuno
BACKGROUND: SRC kinase (SRC proto-oncogene, non-receptor tyrosine kinase) is a promising target for the treatment of solid cancers including human melanoma. Bosutinib (Bosu), a SRC inhibitor, has already been applied to the treatment of human chronic myelogenous leukemia and also has been assessed its safety in dogs. AIM: The aim of this study was to clarify a novel anti-tumour mechanism of Bosu in canine and human melanoma cells. MATERIALS AND METHODS: The canine and human melanoma cells were treated with Bosu and its effects were evaluated by the cell viability, the protein expression levels such as caspase-3 and LC3, Annexin V/Propidium iodide staining, and confocal immunostaining...
March 28, 2017: Veterinary and Comparative Oncology
https://www.readbyqxmd.com/read/28368422/abl-kinase-regulation-by-braf-erk-and-cooperation-with-akt-in-melanoma
#17
A Jain, R Tripathi, C P Turpin, C Wang, R Plattner
The melanoma incidence continues to increase, and the disease remains incurable for many due to its metastatic nature and high rate of therapeutic resistance. In particular, melanomas harboring BRAF(V600E) and PTEN mutations often are resistant to current therapies, including BRAF inhibitors (BRAFi) and immune checkpoint inhibitors. Abl kinases (Abl/Arg) are activated in melanomas and drive progression; however, their mechanism of activation has not been established. Here we elucidate a novel link between BRAF(V600E)/ERK signaling and Abl kinases...
April 3, 2017: Oncogene
https://www.readbyqxmd.com/read/28368000/src-family-kinases-fyn-and-lyn-are-constitutively-activated-and-mediate-plasmacytoid-dendritic-cell-responses
#18
S Dallari, M Macal, M E Loureiro, Y Jo, L Swanson, C Hesser, P Ghosh, E I Zuniga
Plasmacytoid dendritic cells (pDC) are type I interferon-producing cells with critical functions in a number of human illnesses; however, their molecular regulation is incompletely understood. Here we show the role of Src family kinases (SFK) in mouse and human pDCs. pDCs express Fyn and Lyn and their activating residues are phosphorylated both before and after Toll-like receptor (TLR) stimulation. Fyn or Lyn genetic ablation as well as treatment with SFK inhibitors ablate pDC (but not conventional DC) responses both in vitro and in vivo...
April 3, 2017: Nature Communications
https://www.readbyqxmd.com/read/28367061/focal-adhesion-kinases-crucially-regulate-tgf%C3%AE-induced-migration-and-invasion-of-bladder-cancer-cells-via-src-kinase-and-e-cadherin
#19
De-Bo Kong, Feng Chen, Ni Sima
Focal adhesion kinase (FAK) is a non-receptor protein-tyrosine kinase that is triggered off by special extracellular signals such as some growth factors and integrins. FAK is found in cell-matrix attachment sites and implicated in cell migration, invasion, movement, gene expression, survival and apoptosis. In this study, we aimed to investigate whether FAK plays a role in invasion and migration of bladder cancer cells. Using an FAK-specific small interfering RNA (siRNA) and an FAK inhibitor PF-228, we found that inhibition of FAK tyrosine phosphorylation or knockdown of FAK suppressed invasion and migration of bladder cancer cells...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28363904/hydrogen-peroxide-triggers-a-dual-signaling-axis-to-selectively-suppress-activated-human-t-lymphocyte-migration
#20
Jennifer A Ball, Isabella Vlisidou, Matthew D Blunt, Will Wood, Stephen G Ward
H2O2 is an early danger cue required for innate immune cell recruitment to wounds. To date, little is known about whether H2O2 is required for the migration of human adaptive immune cells to sites of inflammation. However, oxidative stress is known to impair T cell activity, induce actin stiffness, and inhibit cell polarization. In this study, we show that low oxidative concentrations of H2O2 also impede chemokinesis and chemotaxis of previously activated human T cells to CXCL11, but not CXCL10 or CXCL12. We show that this deficiency in migration is due to a reduction in inflammatory chemokine receptor CXCR3 surface expression and cellular activation of lipid phosphatase SHIP-1...
May 1, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
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