المؤلفون: Rula Atwani, Rohit Pravin Nagare, Amber Rogers, Mayuri Prasad, Virginie Lazar, George Sandusky, Yan Tong, Fabrizio Pin, Salvatore Condello

المصدر: Journal of Experimental & Clinical Cancer Research, Vol 43, Iss 1, Pp 1-20 (2024)

مصطلحات موضوعية: Beta-catenin, cancer stem cells, Frizzled 7, integrin-linked kinase, ovarian cancer, Chemoresistance, Tumor microenvironment, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Abstract Background Platinum-based chemotherapy regimens are a mainstay in the management of ovarian cancer (OC), but emergence of chemoresistance poses a significant clinical challenge. The persistence of ovarian cancer stem cells (OCSCs) at the end of primary treatment contributes to disease recurrence. Here, we hypothesized that the extracellular matrix protects CSCs during chemotherapy and supports their tumorigenic functions by activating integrin-linked kinase (ILK), a key enzyme in drug resistance. Methods TCGA datasets and OC models were investigated using an integrated proteomic and gene expression analysis and examined ILK for correlations with chemoresistance pathways and clinical outcomes. Canonical Wnt pathway components, pro-survival signaling, and stemness were examined using OC models. To investigate the role of ILK in the OCSC-phenotype, a novel pharmacological inhibitor of ILK in combination with carboplatin was utilized in vitro and in vivo OC models. Results In response to increased fibronectin secretion and integrin β1 clustering, aberrant ILK activation supported the OCSC phenotype, contributing to OC spheroid proliferation and reduced response to platinum treatment. Complexes formed by ILK with the Wnt receptor frizzled 7 (Fzd7) were detected in tumors and correlated with metastatic progression. Moreover, TCGA datasets confirmed that combined expression of ILK and Fzd7 in high grade serous ovarian tumors is correlated with reduced response to chemotherapy and poor patient outcomes. Mechanistically, interaction of ILK with Fzd7 increased the response to Wnt ligands, thereby amplifying the stemness-associated Wnt/β-catenin signaling. Notably, preclinical studies showed that the novel ILK inhibitor compound 22 (cpd-22) alone disrupted ILK interaction with Fzd7 and CSC proliferation as spheroids. Furthermore, when combined with carboplatin, this disruption led to sustained AKT inhibition, apoptotic damage in OCSCs and reduced tumorigenicity in mice. Conclusions This “outside-in” signaling mechanism is potentially actionable, and combined targeting of ILK-Fzd7 may lead to new therapeutic approaches to eradicate OCSCs and improve patient outcomes.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1756-9966Test

الوصول الحر: https://doaj.org/article/61ab184379fa418987004cdab1fef9eeTest

المؤلفون: Atwani, Rula, Rogers, Amber, Nagare, Rohit, Prasad, Mayuri, Lazar, Virginie, Sandusky, George, Pin, Fabrizio, Condello, Salvatore

المساهمون: Obstetrics and Gynecology, School of Medicine

المصدر: PMC

مصطلحات موضوعية: Beta-catenin, Cancer stem cells, Chemoresistance, Frizzled 7, Integrin-linked kinase, Ovarian cancer, Tumor microenvironment

الوصف: Background: Platinum-based chemotherapy regimens are a mainstay in the management of ovarian cancer (OC), but emergence of chemoresistance poses a significant clinical challenge. The persistence of ovarian cancer stem cells (OCSCs) at the end of primary treatment contributes to disease recurrence. Here, we hypothesized that the extracellular matrix protects CSCs during chemotherapy and supports their tumorigenic functions by activating integrin-linked kinase (ILK), a key enzyme in drug resistance. Methods: TCGA datasets and OC models were investigated using an integrated proteomic and gene expression analysis and examined ILK for correlations with chemoresistance pathways and clinical outcomes. Canonical Wnt pathway components, pro-survival signaling, and stemness were examined using OC models. To investigate the role of ILK in the OCSC-phenotype, a novel pharmacological inhibitor of ILK in combination with carboplatin was utilized in vitro and in vivo OC models. Results: In response to increased fibronectin (FN) secretion and integrin β1 clustering, aberrant ILK activation supported the OCSC phenotype, contributing to OC spheroid proliferation and reduced response to platinum treatment. Complexes formed by ILK with the Wnt receptor frizzled 7 (Fzd7) were detected in tumors and showed a strong correlation with metastatic progression. Moreover, TCGA datasets confirmed that combined expression of ILK and Fzd7 in high grade serous ovarian tumors is correlated with reduced response to chemotherapy and poor patient outcomes. Mechanistically, interaction of ILK with Fzd7 increased the response to Wnt ligands, thereby amplifying the stemness-associated Wnt/β-catenin signaling. Notably, preclinical studies showed that the novel ILK inhibitor compound 22 (cpd-22) alone disrupted ILK interaction with Fzd7 and CSC proliferation as spheroids. Furthermore, when combined with carboplatin, this disruption led to sustained AKT inhibition, apoptotic damage in OCSCs and reduced tumorigenicity in mice. Conclusions: This ...

وصف الملف: application/pdf

العلاقة: Atwani R, Rogers A, Nagare R, et al. Integrin-linked kinase-frizzled 7 interaction maintains cancer stem cells to drive platinum resistance in ovarian cancer. Preprint. Res Sq. 2024;rs.3.rs-4086737. Published 2024 Mar 13. doi:10.21203/rs.3.rs-4086737/v1; https://hdl.handle.net/1805/41890Test

الإتاحة: https://doi.org/10.21203/rs.3.rs-4086737/v1Test
https://hdl.handle.net/1805/41890Test

المؤلفون: Daewon Kim, Gary Stacey

المصدر: Plant Signaling & Behavior, Vol 18, Iss 1 (2023)

مصطلحات موضوعية: extracellular atp, purinergic signaling, p2k2, purinoreceptor, integrin-linked kinase 5 (ilk5), danger-associated molecular patterns (damps), Plant ecology, QK900-989, Biology (General), QH301-705.5

الوصف: Extracellular ATP (eATP) in plants plays a crucial role as a ligand for purinoreceptors, mediating purinergic signaling and regulating diverse biological functions, including responses to abiotic and biotic stresses. DORN1/P2K1 (LecRK I.9) was the first identified plant purinoreceptor. P2K2 (LecRK I.5) was subsequently identified as an additional plant purinoreceptor and shown to directly interact with P2K1. Recently, we reported that P2K1 interacts with Integrin-linked kinase 5 (ILK5), a Raf-like MAPKKK protein, and phosphorylates ILK5 to regulate purinergic signaling in relation to plant innate immunity. Here, we report that P2K2 also interacts with the ILK5 protein in planta. Furthermore, we demonstrate that P2K2 phosphorylates ILK5 in the presence of [γ-32P] ATP, similar to P2K1. However, unlike P2K1, P2K2 exhibits strong phosphorylation even when the Serine 192 residue of ILK5 is mutated to Alanine (ILK5S192A), suggesting the possibility of phosphorylation of other residues to fully regulate ILK5 protein function.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1559-2316Test; https://doaj.org/toc/1559-2324Test

الوصول الحر: https://doaj.org/article/73f3fe9d67ca4aba924ca88776786cb0Test

المؤلفون: Maria Delgado-Marin, Sandra Sánchez-Esteban, Alberto Cook-Calvete, Sara Jorquera-Ortega, Carlos Zaragoza, Marta Saura

المصدر: Cells, Vol 13, Iss 6, p 481 (2024)

مصطلحات موضوعية: valve endothelial cells, calcific valve disease, chronic kidney disease, indoxyl sulfate, cell transdifferentiation, integrin-linked kinase, Cytology, QH573-671

الوصف: Calcific Aortic Valve Disease (CAVD) is a significant concern for cardiovascular health and is closely associated with chronic kidney disease (CKD). Aortic valve endothelial cells (VECs) play a significant role in the onset and progression of CAVD. Previous research has suggested that uremic toxins, particularly indoxyl sulfate (IS), induce vascular calcification and endothelial dysfunction, but the effect of IS on valve endothelial cells (VECs) and its contribution to CAVD is unclear. Our results show that IS reduced human VEC viability and increased pro-calcific markers RUNX2 and alkaline phosphatase (ALP) expression. Additionally, IS-exposed VECs cultured in pro-osteogenic media showed increased calcification. Mechanistically, IS induced endothelial-to-mesenchymal transition (EndMT), evidenced by the loss of endothelial markers and increased expression of mesenchymal markers. IS triggered VEC inflammation, as revealed by NF-kB activation, and decreased integrin-linked kinase (ILK) expression. ILK overexpression reversed the loss of endothelial phenotype and RUNX2, emphasizing its relevance in the pathogenesis of CAVD in CKD. Conversely, a lower dose of IS intensified some of the effects in EndMT caused by silencing ILK. These findings imply that IS affects valve endothelium directly, contributing to CAVD by inducing EndMT and calcification, with ILK acting as a crucial modulator.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/2073-4409/13/6/481Test; https://doaj.org/toc/2073-4409Test

الوصول الحر: https://doaj.org/article/57cba92b68024a8297406e44c62f7aa3Test

المؤلفون: Shatha M. Alobaid, Rahaf M. Alshahrani, Asma S. Alonazi, Nawal M. Alrasheed, Maha A. Alamin, Tahani K. Alshammari, Anfal F. Bin Dayel, Doaa M. Elnagar, Rana R. Alotaibi, Lama A. Almuthnabi, Dalia H. Almasud, Shahad E. Al-Ammar, Shahad O. Almadhi, Reema A. Almalke, Nouf T. Aldamri, Hanan K. Alghibiwi, Dalal A. Alkhelb, Nouf M. Alrasheed

المصدر: Pharmaceuticals, Vol 17, Iss 3, p 374 (2024)

مصطلحات موضوعية: glucagon-like peptide-1 analog, diabetic cardiomyopathy, streptozotocin-induced type 2 diabetes, integrin-linked kinase, phosphatidylinositol 3-kinase, protein kinase B, Medicine, Pharmacy and materia medica, RS1-441

الوصف: One of the possible candidates for the treatment of diabetic cardiomyopathy is liraglutide, a glucagon-like peptide-1 receptor (GLP1R) agonist. In this study, the impacts of liraglutide on the integrin-linked kinase (ILK)-related PI3K/AKT axis in rats with type 2 diabetes induced via streptozotocin were examined. Twenty-four Wistar albino rats were distributed in four different groups, and a high-fat diet and streptozotocin were used to induce type 2 in two groups. Rats in the untreated control groups were administered 0.9% NaCl solution over a 6-week period, and those in the treatment groups were administered 0.9% NaCl for 3 weeks, followed by subcutaneous injection of liraglutide (150 μg/kg) for an additional 3 weeks. In the liraglutide-treated diabetic group, the heart-to-body weight ratio was significantly reduced, levels of cardiac biomarkers, troponin I and creatine-kinase-MB, were improved; activities of antioxidant enzymes, glutathione peroxidase and superoxide dismutase, were increased; and levels of malondialdehyde were decreased. Western blotting and immunohistochemical studies revealed increased levels of ILK, P-PI3K, P-AKT, and BCL2, as well as those of caspase 3, BAX, and P-PTEN, indicating mitigation of cardiomyocyte apoptosis. Our results show that liraglutide, by targeting GLP1Rs, enhances the expression of proteins in the ILK/PI3K/AKT/PTEN pathway and thereby exerts its cardioprotective effects in rats with DCM.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/1424-8247/17/3/374Test; https://doaj.org/toc/1424-8247Test

الوصول الحر: https://doaj.org/article/095cdbd134b645aaadab72aa3b31cd32Test

المؤلفون: Nawal M. Alrasheed, Raghad B. Alammari, Tahani K. Alshammari, Maha A. Alamin, Abeer O. Alharbi, Asma S. Alonazi, Anfal F. Bin Dayel, Nouf M. Alrasheed

المصدر: BMC Cardiovascular Disorders, Vol 23, Iss 1, Pp 1-14 (2023)

مصطلحات موضوعية: Tamsulosin, Myocardial infarction, Integrin-linked kinase, Fibrosis, Isoproterenol, Diseases of the circulatory (Cardiovascular) system, RC666-701

الوصف: Abstract Background Myocardial infarction (MI) is considered a public health problem. According to the World Health Organization, MI is a leading cause of death and comorbidities worldwide. Activation of the α1A adrenergic receptor is a contributing factor to the development of MI. Tamsulosin, an α1A adrenergic blocker, has gained wide popularity as a medication for the treatment of benign prostatic hyperplasia. Limited evidence from previous studies has revealed the potential cardioprotective effects of tamsulosin, as its inhibitory effect on the α1A adrenoceptor protects the heart by acting on the smooth muscle of blood vessels, which results in hypotension; however, its effect on the infarcted heart is still unclear. The mechanisms of the expected cardioprotective effects mediated by tamsulosin are not yet understood. Transforming growth factor-beta (TGF-β), a mediator of fibrosis, is considered an attractive therapeutic target for remodeling after MI. The role of α1A adrenoceptor inhibition or its relationships with integrin-linked kinase (ILK) and TGF-β/small mothers against decapentaplegic (Smad) signaling pathways in attenuating MI are unclear. The present study was designed to investigate whether tamsulosin attenuates MI by modulating an ILK-related TGF-β/Smad pathway. Methods Twenty-four adult male Wistar rats were randomly divided into 4 groups: control, ISO, TAM, and ISO + TAM. ISO (150 mg/kg, intraperitoneally) was injected on Days 20 and 21 to induce MI. Tamsulosin (0.8 mg/kg, orally) was administered for 21 days, prior to ISO injection for 2 consecutive days. Heart-to-body weight ratios and cardiac and fibrotic biomarker levels were subsequently determined. ILK, TGF-β1, p-Smad2/3, and collagen III protein expression levels were determined using biomolecular methods. Results Tamsulosin significantly attenuated the relative heart-to-body weight index (p

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1471-2261Test

الوصول الحر: https://doaj.org/article/45034a95f90549b2bf5967daa7fc6e95Test

المؤلفون: Mercedes Castro-Pinto, José López-Menéndez, Sandra Sánchez-Esteban, Ignacio Hernández, Paula Reventún, Jorge Rodríguez-Roda, Carlos Zaragoza, Marta Saura

المصدر: Cirugía Cardiovascular, Vol 30, Iss 1, Pp 11-16 (2023)

مصطلحات موضوعية: Aortic stenosis, Calcification, Integrin-linked kinase, Nitric oxide, Endothelial dysfunction, Medicine, Surgery, RD1-811

الوصف: Resumen: Introducción y objetivos: La quinasa ligada a integrina (ILK) endotelial controla la producción del óxido nítrico, modulando señales de transducción al interior celular. La disminución de ILK endotelial se ha relacionado con la calcificación valvular. Analizamos la asociación de la ILK con la calcificación de la válvula aórtica. Métodos: Estudio observacional, unicéntrico y prospectivo. Recogimos tejido valvular aórtico de pacientes intervenidos de estenosis aórtica, y controles de válvulas no calcificadas. Cuantificamos los niveles de ILK endotelial empleando técnicas de análisis molecular, así como marcadores de crecimiento óseo (BMP2 y RUNX2). Para el control de factores de confusión empleamos regresión logística múltiple por pasos, introduciendo parámetros relacionados con la aterosclerosis y calcificación valvular (edad, DM, HTA, insuficiencia renal). Resultados: Obtuvimos muestras de 75 pacientes y 28 controles. El 69,9% eran varones, la edad media fue de 67 años (DE 9,59 años). Los niveles de ILK fueron significativamente más bajos en válvulas patológicas que en controles (0,96 vs. 0,76; p

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S1134009622001656Test; https://doaj.org/toc/1134-0096Test

الوصول الحر: https://doaj.org/article/5ffb1079fe9c4e70a77dce3802b82a37Test

المؤلفون: Domínguez Solà, David

المساهمون: University/Department: Universitat Pompeu Fabra. Departament de Ciències Experimentals i de la Salut

مرشدي الرسالة: García de Herreros, Antonio

المصدر: TDX (Tesis Doctorals en Xarxa)

مصطلحات موضوعية: Polimerització in vitro, PKCzeta, PKC atípica (Protein Kinase C), P65, Promotor, Nocodazol, NF-kB/Dorsal (Nuclear Factor Kappa-B), NES (seqüència d'export nuclear), Migració MIZ-1(Myc Interacting Zinc Finger Protein, Microtúbuls detirosinats, Microtúbuls, Metàstasi, Invasió, Adenocarcinoma, APC (Proteïna de la Poliposi Adenomatosa Colònica), ARNm, Beta-catenina, Centrosoma, CLIP-170, Cancer, Cresta neural, CRM1 (Chromosome Region Maintenance 1), Despolimerització microtúbuls, Dit de Zenc atípic, Dit de Zenc, Domini ric en Serines, Ebox, E-cadherina, Espais intercromatínics, Estabilització microtúbuls, Export nuclear, Factor de processament de l'ARNm (Factor d'splicin, Filaments intermediaris, Fosforilació, Gastrulació, GFP (Green Fluorescent Protein), Heterocarions, ILK (Integrin Linked Kinase), Reconstrucció fronts invasius, Regulació, Retrogen, RhoA, GTPasa, SC35, Slug, SNAG (domini), SNAI1L, Snail, Speckles nuclears, Time-lapse, TPA (tetradecanoyl-phorbol myristate acetate), Èster de forbol, Transició Epiteli-Mesènquima, Transcripció / Transcripcional, U2AF65, Unions intercel·lulars (Unions adherents), Vimentina

الوصف: Els factors de transcripció de la família Snail són fonamentals en la "transició epiteli-mesènquima", procés morfogènic essencial en el desenvolupament embrionari i en els fenòmens metastàsics tumorals.En els mamífers l'activitat d'Snail és modulada per dos mecanismes. (i) En el promotor humà es troben regions definides de resposta a factors repressors, predominants en les cèl·lules epitelials, i elements diferenciats de resposta a inductors de la "transició epiteli-mesènquima". (ii) L'activitat d'Snail és condicionada també per la seva localització subcel·lular, modulada per mecanismes no transcripcionals: la fosforilació d'Snail determina si és o no exclós del nucli. Al citosol no pot actuar com a repressor transcripcional però pot interaccionar amb la xarxa microtubular, que estabilitza i en condiciona el dinamisme. Això coincideix amb l'activació de la GTPasa RhoA i la reorientació dels filaments de vimentina, fets associats a l'adquisició de capacitat migratòria. L'efecte com a repressor transcripcional i la modulació del dinamisme microtubular són possiblement esdeveniments coordinats necessaris per al rol biològic d'Snail en mamífers.

الوصف (مترجم): Snail family of transcription factors is fundamental to the "epithelial-mesenchymal transition", morphogenic process essential to embryonic development and metastatic phenomena in tumors.Snail's activity is modulated in two ways in mammals. (i) The human promoter harbors definite regions that respond to repressor factors, which prevail in epithelial cells; and differentiated elements that respond to known inducers of the "epithelial-mesenchymal transition". (ii) Snail's activity is also conditioned by its subcellular localization, mechanism not dependent on its transcriptional control: Snail phosphorylation determines whether Snail is excluded or not from the nucleus. When in the cytosol, Snail is unable to act as a transcriptional repressor, but however binds to the microtubular meshwork, which becomes stabilized and whose dynamism is conditioned as a result. This fact coincides with the activation of the RhoA GTPase and reorientation of vimentin filaments, both phenomena being related to the acquisition of cell motility. The transcriptional repressor and the microtubule dynamics effects are probably two coordinated events necessary to Snail's biological role in mammals.
Programa de doctorat en Biomedicina

وصف الملف: application/pdf

الوصول الحر: http://www.tdx.cat/TDX-0516103-123917Test
http://hdl.handle.net/10803/7065Test

المؤلفون: Deeptarup Biswas, Ankit Halder, Abhilash Barpanda, Susmita Ghosh, Aparna Chauhan, Lipika Bhat, Sridhar Epari, Prakash Shetty, Aliasgar Moiyadi, Graham Roy Ball, Sanjeeva Srivastava

المصدر: Cells, Vol 12, Iss 20, p 2483 (2023)

مصطلحات موضوعية: meningioma, integrin-linked kinase (ILK), extracellular matrix organization (EMO), proteomics, transcriptomics, apoptosis, Cytology, QH573-671

الوصف: Meningioma, a primary brain tumor, is commonly encountered and accounts for 39% of overall CNS tumors. Despite significant progress in clinical research, conventional surgical and clinical interventions remain the primary treatment options for meningioma. Several proteomics and transcriptomics studies have identified potential markers and altered biological pathways; however, comprehensive exploration and data integration can help to achieve an in-depth understanding of the altered pathobiology. This study applied integrated meta-analysis strategies to proteomic and transcriptomic datasets comprising 48 tissue samples, identifying around 1832 common genes/proteins to explore the underlying mechanism in high-grade meningioma tumorigenesis. The in silico pathway analysis indicated the roles of extracellular matrix organization (EMO) and integrin binding cascades in regulating the apoptosis, angiogenesis, and proliferation responsible for the pathobiology. Subsequently, the expression of pathway components was validated in an independent cohort of 32 fresh frozen tissue samples using multiple reaction monitoring (MRM), confirming their expression in high-grade meningioma. Furthermore, proteome-level changes in EMO and integrin cell surface interactions were investigated in a high-grade meningioma (IOMM-Lee) cell line by inhibiting integrin-linked kinase (ILK). Inhibition of ILK by administrating Cpd22 demonstrated an anti-proliferative effect, inducing apoptosis and downregulating proteins associated with proliferation and metastasis, which provides mechanistic insight into the disease pathophysiology.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/2073-4409/12/20/2483Test; https://doaj.org/toc/2073-4409Test

الوصول الحر: https://doaj.org/article/de3e323aa37c4f0ea76ccbf5c85dea4cTest

المؤلفون: Mousavizadeh, Rouhollah¹, Hojabrpour, Payman², Eltit, Felipe³, McDonald, Paul C.⁴, Dedhar, Shoukat^4,5, McCormack, Robert G.⁶, Duronio, Vincent², Jafarnejad, Seyed Mehdi⁷, Scott, Alex¹ alex.scott@ubc.ca

المصدر: Scientific Reports. 7/28/2020, Vol. 10 Issue 1, p1-12. 12p.

مصطلحات موضوعية: *INTEGRIN-linked kinase, *MTOR protein, *COLLAGEN, *PROTEIN synthesis, *TENDONS, *FIBROBLASTS

مستخلص: Tendons are specialized tissues composed primarily of load-responsive fibroblasts (tenocytes) embedded in a collagen-rich extracellular matrix. Habitual mechanical loading or targeted exercise causes tendon cells to increase the stiffness of the extracellular matrix; this adaptation may occur in part through collagen synthesis or remodeling. Integrins are likely to play an important role in transmitting mechanical stimuli from the extracellular matrix to tendon cells, thereby triggering cell signaling pathways which lead to adaptive regulation of mRNA translation and protein synthesis. In this study, we discovered that mechanical stimulation of integrin β1 leads to the phosphorylation of AKT, an event which required the presence of integrin-linked kinase (ILK). Repetitive stretching of tendon cells activates the AKT and mTOR pathways, which in turn regulates mRNA translation and collagen expression. These results support a model in which integrins are an upstream component of the mechanosensory cellular apparatus, regulating fundamental tendon cell functions relevant to exercise-induced adaptation and mechanotherapy. [ABSTRACT FROM AUTHOR]