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gamma secretase

Tushar D Bhagat, Yiyu Zou, Shizeng Huang, Jihwan Park, Matthew B Palmer, Caroline Hu, Wejuan Li, Niraj Shenoy, Orsolya Giricz, Gaurav Choudhary, Yiting Yu, Yi-An Ko, Maria C Izquierdo, Ae Seo Deok Park, Nishanth Vallumsetla, Remi Laurence, Robert Lopez, Masako Suzuki, James Pullman, Justin Kaner, Benjamin Gartrell, A Ari Hakimi, John M Greally, Bharvin Patel, Karim Benhadji, Kith Pradhan, Amit Verma, Katalin Susztak
Clear cell renal cell carcinoma (CCRCC) is an incurable malignancy in advanced stages and needs newer therapeutic targets. Transcriptomic analysis of CCRCCs and matched microdissected renal tubular controls revealed overexpression of NOTCH ligands and receptors in tumor tissues. Examination of the TCGA RNA-seq dataset also revealed widespread activation of NOTCH pathway in a large cohort of CCRCC samples. Samples with NOTCH pathway activation were also clinically distinct and were associated with better overall survival...
December 1, 2016: Journal of Biological Chemistry
M C Pazos, D Abramovich, A Bechis, P Accialini, F Parborell, M Tesone, G Irusta
Ovarian cancer is characterized by being highly metastatic, a feature that represents the main cause of failure of the treatment. This study investigated the effects of γ-secretase inhibition on the TGF-β-induced epithelial-mesenchymal transition (EMT) process in ovarian cancer cell lines. SKOV3 cells incubated in the presence of TGF-β showed morphological and biochemical changes related to EMT, which were blocked by co-stimulation with TGF-β and the γ-secretase inhibitor DAPT. In SKOV3 and IGROV1 cells, the co-stimulation blocked the cadherin switch and the increase in the transcription factors Snail, Slug, Twist and Zeb1 induced by TGF-β...
November 28, 2016: Molecular and Cellular Endocrinology
Marzia A Locatelli, Philippe Aftimos, E Claire Dees, Patricia M LoRusso, Mark D Pegram, Ahmad Awada, Bo Huang, Rossano Cesari, Yuqiu Jiang, M Naveed Shaik, Kenneth A Kern, Giuseppe Curigliano
BACKGROUND: The NOTCH signaling pathway may be involved in the survival of stem cell-like tumor-initiating cells and contribute to tumor growth. In this phase Ib, open-label, multicenter study (NCT01876251), we evaluated PF-03084014, a selective gamma-secretase inhibitor in patients with advanced triple-negative breast cancer. METHODS: The dose-finding part was based on a 2×3 matrix design using the modified toxicity probability interval method. Oral PF-03084014 was administered twice daily continuously in combination with intravenous docetaxel given on day 1 of each 21-day cycle...
November 30, 2016: Oncotarget
X N Yang, X J Liu, L T Zhao, X L Zeng, H R Bao
Objective: To explore the role of Notch signaling pathway on immune imbalance in chronic obstructive pulmonary disease (COPD). Methods: Thirty BALB/c mice were randomly assigned into the healthy control group, COPD group, and COPD Gamma secretase inhibitors (GSI) group. Cigarette smoke exposure was used to establish the COPD model. T cells were enriched by filtering through nylon wool columns. The proportion of spleen-derived T-lymphocyte subsets was detected by flow cytometry. Real-time quantitative polymerase chain reaction (RT-PCR) and Western blot (WB) were used to detect the expression of splenic T cells' Notch1 and its downstream Hes1 mRNA and protein respectively...
November 12, 2016: Chinese Journal of Tuberculosis and Respiratory Diseases
Alexandre Vallée, Yves Lecarpentier
The molecular mechanisms underlying the pathophysiology of Alzheimer's disease (AD) are still not fully understood. In AD, Wnt/beta-catenin signaling has been shown to be downregulated while the peroxisome proliferator-activated receptor (PPAR) gamma (mARN and protein) is upregulated. Certain neurodegenerative diseases share the same Wnt/beta-catenin/PPAR gamma profile, such as bipolar disorder and schizophrenia. Conversely, other NDs share an opposite profile, such as amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, multiple sclerosis, and Friedreich's ataxia...
2016: Frontiers in Neuroscience
Michael Rehman, Sreeharsha Gurrapu, Gabriella Cagnoni, Lorena Capparuccia, Luca Tamagnone
The secreted semaphorin Sema3E controls cell migration and invasiveness in cancer cells. Sema3E-receptor, PlexinD1, is frequently upregulated in melanoma, breast, colon, ovarian and prostate cancers; however, the mechanisms underlying PlexinD1 upregulation and the downstream events elicited in tumor cells are still unclear. Here we show that the canonical RBPjk-dependent Notch signaling cascade controls PlexinD1 expression in primary endothelial and cancer cells. Transcriptional activation was studied by quantitative PCR and promoter activity reporter assays...
2016: PloS One
Mark Y Chiang, Qing Wang, Anna C Gormley, Sarah J Stein, Lanwei Xu, Olga Shestova, Jon C Aster, Warren S Pear
Activating NOTCH1 mutations are frequent in human T-cell acute lymphoblastic leukemia (T-ALL) and Notch inhibitors (γ-secretase inhibitors [GSIs]) have produced responses in patients with relapsed, refractory disease. However, sustained responses, although reported, are uncommon, suggesting that other pathways can substitute for Notch in T-ALL. To address this possibility, we first generated Kras(G12D) transgenic mice with T-cell-specific expression of the pan-Notch inhibitor, dominant-negative Mastermind (DNMAML)...
November 3, 2016: Blood
Viola Lanier, Corey Gillespie, Merle Leffers, Danielle Daley-Brown, Joy Milner, Crystal Lipsey, Nia Webb, Leonard M Anderson, Gale Newman, Johannes Waltenberger, Ruben Rene Gonzalez-Perez
Leptin increases vascular endothelial growth factor (VEGF), VEGF receptor-2 (VEGFR-2), and Notch expression in cancer cells, and transphosphorylates VEGFR-2 in endothelial cells. However, the mechanisms involved in leptin's actions in endothelial cells are not completely known. Here we investigated whether a leptin-VEGFR-Notch axis is involved in these leptin's actions. To this end, human umbilical vein and porcine aortic endothelial cells (wild type and genetically modified to overexpress VEGFR-1 or -2) were cultured in the absence of VEGF and treated with leptin and inhibitors of Notch (gamma-secretase inhibitors: DAPT and S2188, and silencing RNA), VEGFR (kinase inhibitor: SU5416, and silencing RNA) and leptin receptor, OB-R (pegylated leptin peptide receptor antagonist 2: PEG-LPrA2)...
October 2016: International Journal of Biochemistry & Cell Biology
Rui D Mendes, Kirsten Canté-Barrett, Rob Pieters, Jules P P Meijerink
The tumor suppressor phosphatase and tensin homolog (PTEN) negatively regulates phosphatidylinositol 3-kinase (PI3K)-AKT signaling and is often inactivated by mutations (including deletions) in a variety of cancer types, including T-cell acute lymphoblastic leukemia. Here we review mutation-associated mechanisms that inactivate PTEN together with other molecular mechanisms that activate AKT and contribute to T-cell leukemogenesis. In addition, we discuss how Pten mutations in mouse models affect the efficacy of gamma-secretase inhibitors to block NOTCH1 signaling through activation of AKT...
September 2016: Haematologica
Jiunn-Ren Wu, Jwu-Lai Yeh, Shu-Fen Liou, Zen-Kong Dai, Bin-Nan Wu, Jong-Hau Hsu
Patent ductus arteriosus (PDA) can cause morbidity and mortality in neonates. Vascular remodeling, characterized by proliferation and migration of smooth muscle cells (SMCs), is an essential process for postnatal DA closure. Notch signaling is an important mediator of vascular remodelling but its role in DA is unkonwn. We investigated the effects and underlying mechanisms of γ-secretase inhibitor DAPT, a Notch signaling inhibitor on angiotensin II (Ang II)-induced proliferation and migration of DASMCs. Proliferation and migration of DASMCs cultured from neonatal Wistar rats were induced by Ang II, with or without DAPT pre-treatment...
2016: International Journal of Biological Sciences
Paul B Rosenberg, Krista L Lanctôt, Nathan Herrmann, Jacobo E Mintzer, Anton P Porsteinsson, Xiaoying Sun, Rema Raman
BACKGROUND: In a recent report, 76 weeks' treatment with a gamma-secretase inhibitor (semagacestat) was associated with poorer cognitive outcomes in Alzheimer's disease (AD). OBJECTIVE: We sought to examine the effect of semagacestat treatment on neuropsychiatric symptoms (NPS). METHODS: 1,537 participants with mild to moderate AD were randomized to 76 weeks' treatment with placebo versus two doses of semagacestat. NPS were assessed with the Neuropsychiatric Inventory (NPI-Total and subdomains)...
August 10, 2016: Journal of Alzheimer's Disease: JAD
Yasuyuki Ikezawa, Jun Sakakibara-Konishi, Hidenori Mizugaki, Satoshi Oizumi, Masaharu Nishimura
BACKGROUND: The Notch receptor plays an important role in various cell fate decisions during development and in cancer. We have previously reported that Notch3 is upregulated by radiation in non-small cell lung cancer (NSCLC) cell lines and that the Notch pathway inhibitor γ secretase inhibitor GSI (gamma-secretase inhibitor), when combined with radiation therapy, significantly suppressed the growth of lung cancer cells. However, little is known about the mechanism of Notch upregulation induced by radiation...
August 23, 2016: International Journal of Clinical Oncology
Imma Raurell, Montserrat Codina, David Casagolda, Beatriz Del Valle, Josep Baulida, Antonio García de Herreros, Mireia Duñach
[This corrects the article DOI: 10.1371/journal.pone.0004080.].
2016: PloS One
Noémi Nagy, Melinda Hajdu, Ágnes Márk, Péter Attila Király, Mónika Tóth, Titanilla Dankó, Mónika Csóka, Anna Sebestyén
Growing evidence suggests that deregulation of signalling elements of Notch and mammalian target of rapamycin (mTOR) pathways contribute to tumorigenesis. These signals play important roles in cellular functions and malignancies. Their tumorigenic role in T-cell acute lymphoblastic leukaemia (T-ALL) is well known; however, their potential interactions and functions are poorly characterized in Hodgkin lymphoma (HL). The aim of our study was to characterize mTOR and Notch signalling elements in HL cell lines (DEV, L1236, KMH2) and human biopsies and to investigate their cross-talk in the tumorous process...
July 29, 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Kaushik Ghosal, Qingyuan Fan, Hana N Dawson, Sanjay W Pimplikar
Amyloid precursor protein (APP) is cleaved by gamma-secretase to simultaneously generate amyloid beta (Aβ) and APP Intracellular Domain (AICD) peptides. Aβ plays a pivotal role in Alzheimer's disease (AD) pathogenesis but recent studies suggest that amyloid-independent mechanisms also contribute to the disease. We previously showed that AICD transgenic mice (AICD-Tg) exhibit AD-like features such as tau pathology, aberrant neuronal activity, memory deficits and neurodegeneration in an age-dependent manner...
2016: PloS One
Kevin D Rynearson, Ronald N Buckle, Keith D Barnes, R Jason Herr, Nicholas J Mayhew, William D Paquette, Samuel A Sakwa, Phuong D Nguyen, Graham Johnson, Rudolph E Tanzi, Steven L Wagner
The design and construction of a series of novel aminothiazole-derived γ-secretase modulators is described. The incorporation of heterocyclic replacements of the terminal phenyl D-ring of lead compound 1 was conducted in order to align potency with favorable drug-like properties. γ-Secretase modulator 28 displayed good activity for in vitro inhibition of Aβ42, as well as substantial improvement in ADME and physicochemical properties, including aqueous solubility. Pharmacokinetic evaluation of compound 28 in mice revealed good brain penetration, as well as good clearance, half-life, and volume of distribution which collectively support the continued development of this class of compounds...
August 15, 2016: Bioorganic & Medicinal Chemistry Letters
Pawan Upadhyay, Sudhir Nair, Ekjot Kaur, Jyotirmoi Aich, Prachi Dani, Vidyalakshmi Sethunath, Nilesh Gardi, Pratik Chandrani, Mukul Godbole, Kavita Sonawane, Ratnam Prasad, Sadhana Kannan, Beamon Agarwal, Shubhada Kane, Sudeep Gupta, Shilpee Dutt, Amit Dutt
BACKGROUND: Notch pathway plays a complex role depending on cellular contexts: promotes stem cell maintenance or induces terminal differentiation in potential cancer-initiating cells; acts as an oncogene in lymphocytes and mammary tissue or plays a growth-suppressive role in leukemia, liver, skin, and head and neck cancer. Here, we present a novel clinical and functional significance of NOTCH1 alterations in early stage tongue squamous cell carcinoma (TSCC). PATIENTS AND METHODS: We analyzed the Notch signaling pathway in 68 early stage TSCC primary tumor samples by whole exome and transcriptome sequencing, real-time PCR based copy number, expression, immuno-histochemical, followed by cell based biochemical and functional assays...
July 6, 2016: Oncotarget
Siladitta Biswas, Monica Adrian, Jochen Weber, Konstantin Evdokimov, Manuel Winkler, Cyrill Géraud
Leda-1/Pianp is a type I transmembrane protein expressed by CNS cells, murine melanoma cell line B16F10 and rat liver sinusoidal endothelial cells. The early steps of posttranslational modifications of Leda-1/Pianp have been described to include glycosylation and processing by proprotein convertases. Here, we comprehensively characterized the subsequent steps of proteolytic processing of Leda-1/Pianp. For this purpose specific protease inhibitors and cell lines deficient in PS1, PS2, PS1/PS2 and ADAM10/17 were deployed...
September 2, 2016: Biochemical and Biophysical Research Communications
Lizandra G Magalhães, Enyara R Morais, Carla B Machado, Matheus S Gomes, Fernanda J Cabral, Julia M Souza, Cláudia S Soares, Renata G Sá, William Castro-Borges, Vanderlei Rodrigues
Several signaling molecules that govern development in higher animals have been identified in the parasite Schistosoma mansoni, including the transforming growth factor β, protein tyrosine kinases, nuclear hormone receptors, among others. The Notch pathway is a highly conserved signaling mechanism which is involved in a wide variety of developmental processes including embryogenesis and oogenesis in worms and flies. Here we aimed to provide the molecular reconstitution of the Notch pathway in S. mansoni using the available transcriptome and genome databases...
October 2016: Parasitology Research
Alejandro Villarreal, Gerardo Rosciszewski, Veronica Murta, Vanesa Cadena, Vanina Usach, Martin M Dodes-Traian, Patricia Setton-Avruj, Luis H Barbeito, Alberto J Ramos
UNLABELLED: Reactive gliosis involving activation and proliferation of astrocytes and microglia, is a widespread but largely complex and graded glial response to brain injury. Astroglial population has a previously underestimated high heterogeneity with cells differing in their morphology, gene expression profile, and response to injury. Here, we identified a subset of reactive astrocytes isolated from brain focal ischemic lesions that show several atypical characteristics. Ischemia-derived astrocytes (IDAs) were isolated from early ischemic penumbra and core...
2016: Frontiers in Cellular Neuroscience
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