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https://www.readbyqxmd.com/read/28539479/%C3%AE-secretase-inhibitors-in-cancer-clinical-trials-are-pharmacologically-and-functionally-distinct
#1
Yong Ran, Fokhrul Hossain, Antonio Pannuti, Christian B Lessard, Gabriela Z Ladd, Joo In Jung, Lisa M Minter, Barbara A Osborne, Lucio Miele, Todd E Golde
γ-Secretase inhibitors (GSIs) are being actively repurposed as cancer therapeutics based on the premise that inhibition of NOTCH1 signaling in select cancers is therapeutic. Using novel assays to probe effects of GSIs against a broader panel of substrates, we demonstrate that clinical GSIs are pharmacologically distinct. GSIs show differential profiles of inhibition of the various NOTCH substrates, with some enhancing cleavage of other NOTCH substrates at concentrations where NOTCH1 cleavage is inhibited. Several GSIs are also potent inhibitors of select signal peptide peptidase (SPP/SPPL) family members...
May 24, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28534531/unravelling-the-biology-of-sclc-implications-for-therapy
#2
REVIEW
Joshua K Sabari, Benjamin H Lok, James H Laird, John T Poirier, Charles M Rudin
Small-cell lung cancer (SCLC) is an aggressive malignancy associated with a poor prognosis. First-line treatment has remained unchanged for decades, and a paucity of effective treatment options exists for recurrent disease. Nonetheless, advances in our understanding of SCLC biology have led to the development of novel experimental therapies. Poly [ADP-ribose] polymerase (PARP) inhibitors have shown promise in preclinical models, and are under clinical investigation in combination with cytotoxic therapies and inhibitors of cell-cycle checkpoints...
May 23, 2017: Nature Reviews. Clinical Oncology
https://www.readbyqxmd.com/read/28533810/tc003132-is-essential-for-the-follicle-stem-cell-lineage-in-telotrophic-tribolium-oogenesis
#3
Matthias Teuscher, Nadi Ströhlein, Markus Birkenbach, Dorothea Schultheis, Michael Schoppmeier
BACKGROUND: Stem cells are undifferentiated cells with a potential for self-renewal, which are essential to support normal development and homeostasis. To gain insight into the molecular mechanisms underlying adult stem cell biology and organ evolution, we use the telotrophic ovary of the beetle Tribolium. To this end, we participated in a large-scale RNAi screen in the red flour beetle Tribolium, which identified functions in embryonic and postembryonic development for more than half of the Tribolium genes...
2017: Frontiers in Zoology
https://www.readbyqxmd.com/read/28533486/galectin-3-acts-as-an-angiogenic-switch-to-induce-tumor-angiogenesis-via-jagged-1-notch-activation
#4
Sofia Nascimento Dos Santos, Helen Sheldon, Jonathas Xavier Pereira, Christopher Paluch, Esther M Bridges, Márcia Curry El-Cheikh, Adrian L Harris, Emerson Soares Bernardes
Angiogenesis is a coordinated process tightly regulated by the balance between Delta-like-4 (DLL4) and Jagged-1 (JAG1) in endothelial cells. Here we show that galectin-3 (gal-3), a glycan-binding protein secreted by cancer cells under hypoxic conditions, triggers sprouting angiogenesis, assisted by hypoxic changes in the glycosylation status of endothelial cells that enhance binding to gal-3. Galectin-3's proangiogenic functions were found to be predominantly dependent on the Notch ligand JAG1. Differential direct binding to JAG1 was shown by surface plasmon resonance assay...
May 9, 2017: Oncotarget
https://www.readbyqxmd.com/read/28530241/notch-mediated-conversion-of-activated-t-cells-into-stem-cell-memory-like-t-cells-for-adoptive-immunotherapy
#5
Taisuke Kondo, Rimpei Morita, Yuumi Okuzono, Hiroko Nakatsukasa, Takashi Sekiya, Shunsuke Chikuma, Takashi Shichita, Mitsuhiro Kanamori, Masato Kubo, Keiko Koga, Takahiro Miyazaki, Yoshiaki Kassai, Akihiko Yoshimura
Adoptive T-cell immunotherapy is a promising approach to cancer therapy. Stem cell memory T (TSCM) cells have been proposed as a class of long-lived and highly proliferative memory T cells. CD8(+) TSCM cells can be generated in vitro from naive CD8(+) T cells via Wnt signalling; however, methods do not yet exist for inducing TSCM cells from activated or memory T cells. Here, we show a strategy for generating TSCM-like cells in vitro (iTSCM cells) from activated CD4(+) and CD8(+) T cells in mice and humans by coculturing with stromal cells that express a Notch ligand...
May 22, 2017: Nature Communications
https://www.readbyqxmd.com/read/28526832/identification-of-a-novel-chalcone-derivative-that-inhibits-notch-signaling-in-t-cell-acute-lymphoblastic-leukemia
#6
Mattia Mori, Luca Tottone, Deborah Quaglio, Nadezda Zhdanovskaya, Cinzia Ingallina, Marisa Fusto, Francesca Ghirga, Giovanna Peruzzi, Maria Elisa Crestoni, Fabrizio Simeoni, Francesca Giulimondi, Claudio Talora, Bruno Botta, Isabella Screpanti, Rocco Palermo
Notch signaling is considered a rational target in the therapy of several cancers, particularly those harbouring Notch gain of function mutations, including T-cell acute lymphoblastic leukemia (T-ALL). Although currently available Notch-blocking agents are showing anti-tumor activity in preclinical studies, they are not effective in all the patients and often cause severe side-effects, limiting their widespread therapeutic use. Here, by functional and biological analysis of the most representative molecules of an in house library of natural products, we have designed and synthetized the chalcone-derivative 8 possessing Notch inhibitory activity at low micro molar concentration in T-ALL cell lines...
May 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28526735/activated-notch-induced-intratumoral-heterogeneity-drives-lung-cancer
#7
(no author information available yet)
Activated NOTCH signaling is both tumor-suppressive and protumorigenic in SCLC.
May 19, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28525978/notch-ligand-delta-like-1-as-a-novel-molecular-target-in-childhood-neuroblastoma
#8
P Bettinsoli, G Ferrari-Toninelli, S A Bonini, C Prandelli, M Memo
BACKGROUND: Neuroblastoma is the most common extracranial solid malignancy in childhood, responsible for 15% of all pediatric cancer deaths. It is an heterogeneous disease that does not always respond to classical therapy; so the identification of new and specific molecular targets to improve existing therapy is needed. We have previously demonstrated the involvement of the Notch pathway in the onset and progression of neuroblastoma. In this study we further investigated the role of Notch signaling and identified Delta-like 1 (DLL1) as a novel molecular target in neuroblastoma cells with a high degree of MYCN amplification, which is a major oncogenic driver in neuroblastoma...
May 19, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28522590/notch-inhibitor-pf-03084014-inhibits-hepatocellular-carcinoma-growth-and-metastasis-via-suppression-of-cancer-stemness-due-to-reduced-activation-of-notch1-stat3
#9
Chuan Xing Wu, Aimin Xu, Cathy C Zhang, Peter Olson, Lin Chen, Terence K Lee, Tan To Cheung, Chung Mau Lo, Xiao Qi Wang
Aberrant activation of the Notch signaling pathway is implicated in many solid tumors, including hepatocellular carcinoma (HCC), indicating a potential use of Notch inhibitors for treatment. In this study, we investigated the antitumor and antimetastasis efficacy of the novel Notch inhibitor (γ-secretase inhibitor) PF-03084014 in HCC. HCC spherical cells (stem-like cancer cells), a sphere-derived orthotopic tumor model and one patient-derived xenograft (PDX) model were used in our experiment. We demonstrated that PF-03084014 inhibited the self-renewal and proliferation of cancer stem cells...
May 18, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28520736/the-bantam-microrna-acts-through-numb-to-exert-cell-growth-control-and-feedback-regulation-of-notch-in-tumor-forming-stem-cells-in-the-drosophila-brain
#10
Yen-Chi Wu, Kyu-Sun Lee, Yan Song, Stephan Gehrke, Bingwei Lu
Notch (N) signaling is central to the self-renewal of neural stem cells (NSCs) and other tissue stem cells. Its deregulation compromises tissue homeostasis and contributes to tumorigenesis and other diseases. How N regulates stem cell behavior in health and disease is not well understood. Here we show that N regulates bantam (ban) microRNA to impact cell growth, a process key to NSC maintenance and particularly relied upon by tumor-forming cancer stem cells. Notch signaling directly regulates ban expression at the transcriptional level, and ban in turn feedback regulates N activity through negative regulation of the Notch inhibitor Numb...
May 17, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28515436/nimbolide-upregulates-reck-by-targeting-mir-21-and-hif-1%C3%AE-in-cell-lines-and-in-a-hamster-oral-carcinogenesis-model
#11
Jaganathan Kowshik, Rajakishore Mishra, Josephraj Sophia, Satabdi Rautray, Kumaraswamy Anbarasu, G Deepak Reddy, Madhulika Dixit, Sundarasamy Mahalingam, Siddavaram Nagini
Reversion-inducing cysteine-rich protein with Kazal motifs (RECK), a potent inhibitor of matrix metalloproteinases (MMPs) is a common negative target of oncogenic signals and a potential therapeutic target for novel drug development. Here, we show that sequential RECKlessness stimulates angiogenesis and Notch signalling in the 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinogenesis model, a paradigm for oral oncogenesis and chemointervention. We also report the chemotherapeutic effect of nimbolide, a limonoid from the neem tree (Azadirachta indica) based on the upregulation of RECK as well as modulation of the expression of key molecules involved in invasion and angiogenesis...
May 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28507201/sensitivity-of-non-small-cell-lung-cancer-to-erlotinib-is-regulated-by-the-notch-mir-223-fbxw7-pathway
#12
Haiwei Zhang, Fanglin Chen, Yongpeng He, Lin Yi, Chuang Ge, Xiaolong Shi, Chao Tang, Donglin Wang, Yongzhong Wu, Weiqi Nian
Recent evidence supports a role for microRNA-223 (miR-223) in modulating tumor cell sensitivity to chemotherapeutic drugs; however, its role in cellular resistance to the effects of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) used in treatment of non-small cell lung cancer (NSCLC) remains to be elucidated. The levels of miR-223 in parental cell line (HCC827) and erlotinib resistant HCC827 cell line (HCC827/ER)  were detected by qRT-PCR. HCC827/ER cells were treated with MK-2206 to block the Akt signaling pathway or RO4929097 to block the Notch signaling pathway, and then transfected with a miR-223 inhibitor or interference expression plasmid of F-Box/WD repeat-containing protein 7 (FBXW7) or insulin-like growth factor 1 receptor (IGF1R)...
May 15, 2017: Bioscience Reports
https://www.readbyqxmd.com/read/28501774/tuning-of-major-signaling-networks-tgf-%C3%AE-wnt-notch-and-hedgehog-by-mirnas-in-human-stem-cells-commitment-to-different-lineages-possible-clinical-application
#13
REVIEW
Sedigheh Fekri Aval, Hajie Lotfi, Roghayeh Sheervalilou, Nosratollah Zarghami
Two distinguishing characteristics of stem cells, their continuous division in the undifferentiated state and growth into any cell types, are orchestrated by a number of cell signaling pathways. These pathways act as a niche factor in controlling variety of stem cells. The core stem cell signaling pathways include Wingless-type (Wnt), Hedgehog (HH), and Notch. Additionally, they critically regulate the self-renewal and survival of cancer stem cells. Conversely, stem cells' main properties, lineage commitment and stemness, are tightly controlled by epigenetic mechanisms such as DNA methylation, histone modifications and non-coding RNA-mediated regulatory events...
May 11, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28498402/effects-of-runx3-mediated-notch-signaling-pathway-on-biological-characteristics-of-colorectal-cancer-cells
#14
Hang Li, Dan Li, Ning Meng
This study investigated the effects of runt-related transcription factor 3 (RUNX3) mediated Notch pathway on the biological behavior of colorectal cancer (CRC) SW260 cells. CRC tissues and para-carcinoma tissues were collected from 182 CRC patients who had undergone surgical treatment between January 2008 and December 2010. Immunohistochemical staining with streptavidin-peroxidase (SP) was used to detect RUNX3, Notch1 and Jagged 1 expression levels. CRC SW260 cells were divided into the following groups: Control group, si-NC group, si-RUNX3 group, DAPT group, si-RUNX3+DAPT group, and si-NC+DAPT group...
May 8, 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/28493234/exploration-of-involved-key-genes-and-signaling-diversity-in-brain-tumors
#15
REVIEW
Mojdeh Mahdian Nasser, Parvin Mehdipour
Brain tumors are becoming a major cause of death. The classification of brain tumors has gone through restructuring with regard to some criteria such as the presence or absence of a specific genetic alteration in the 2016 central nervous system World Health Organization update. Two categories of genes with a leading role in tumorigenesis and cancer induction include tumor suppressor genes and oncogenes; tumor suppressor genes are inactivated through a variety of mechanisms that result in their loss of function...
May 10, 2017: Cellular and Molecular Neurobiology
https://www.readbyqxmd.com/read/28490670/leukotriene-b4-antagonism-ameliorates-experimental-lymphedema
#16
Wen Tian, Stanley G Rockson, Xinguo Jiang, Jeanna Kim, Adrian Begaye, Eric M Shuffle, Allen B Tu, Matthew Cribb, Zhanna Nepiyushchikh, Abdullah H Feroze, Roham T Zamanian, Gundeep S Dhillon, Norbert F Voelkel, Marc Peters-Golden, Jan Kitajewski, J Brandon Dixon, Mark R Nicolls
Acquired lymphedema is a cancer sequela and a global health problem currently lacking pharmacologic therapy. We have previously demonstrated that ketoprofen, an anti-inflammatory agent with dual 5-lipoxygenase and cyclooxygenase inhibitory properties, effectively reverses histopathology in experimental lymphedema. We show that the therapeutic benefit of ketoprofen is specifically attributable to its inhibition of the 5-lipoxygenase metabolite leukotriene B4 (LTB4). LTB4 antagonism reversed edema, improved lymphatic function, and restored lymphatic architecture in the murine tail model of lymphedema...
May 10, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28489825/intratumoural-heterogeneity-generated-by-notch-signalling-promotes-small-cell-lung-cancer
#17
Jing Shan Lim, Alvaro Ibaseta, Marcus M Fischer, Belinda Cancilla, Gilbert O'Young, Sandra Cristea, Vincent C Luca, Dian Yang, Nadine S Jahchan, Cécile Hamard, Martine Antoine, Marie Wislez, Christina Kong, Jennifer Cain, Yu-Wang Liu, Ann M Kapoun, K Christopher Garcia, Timothy Hoey, Christopher L Murriel, Julien Sage
The Notch signalling pathway mediates cell fate decisions and is tumour suppressive or oncogenic depending on the context. During lung development, Notch pathway activation inhibits the differentiation of precursor cells to a neuroendocrine fate. In small-cell lung cancer, an aggressive neuroendocrine lung cancer, loss-of-function mutations in NOTCH genes and the inhibitory effects of ectopic Notch activation indicate that Notch signalling is tumour suppressive. Here we show that Notch signalling can be both tumour suppressive and pro-tumorigenic in small-cell lung cancer...
May 10, 2017: Nature
https://www.readbyqxmd.com/read/28487384/non-invasive-interrogation-of-dll3-expression-in-metastatic-small-cell-lung-cancer
#18
Sai Kiran Sharma, Jacob Pourat, Dalya Abdel-Atti, Sean D Carlin, Alessandra Piersigilli, Alexander J Bankovich, Eric E Gardner, Omar Hamdy, Kumiko Isse, Sheila Bheddah, Joseph Sandoval, Kristen M Cunanan, Eric B Johansen, Viola Allaj, Vikram Sisodiya, David Liu, Brian M Zeglis, Charles M Rudin, Scott J Dylla, J T Poirier, Jason S Lewis
The Notch ligand DLL3 has emerged as a novel therapeutic target expressed in small cell lung cancer (SCLC) and high-grade neuroendocrine carcinomas. Rovalpituzumab teserine (Rova-T™; SC16LD6.5) is a first-in-class DLL3-targeted antibody-drug conjugate with encouraging initial safety and efficacy profiles in SCLC in the clinic. Here we demonstrate that tumor expression of DLL3, though orders of magnitude lower in surface protein expression than typical oncology targets of immunoPET, can serve as an imaging biomarker for SCLC...
May 9, 2017: Cancer Research
https://www.readbyqxmd.com/read/28487372/structure-function-analysis-of-rbpj-interacting-and-tubulin-associated-rita-reveals-regions-critical-for-repression-of-notch-target-genes
#19
Nassif Tabaja, Zhenyu Yuan, Franz Oswald, Rhett A Kovall
The Notch pathway is a cell-to-cell signaling mechanism that is essential for tissue development and maintenance, and aberrant Notch signaling has been implicated in various cancers, congenital defects, and cardiovascular diseases. Notch signaling activates the expression of target genes, which are regulated by the transcription factor (CBF1/RBP-J, Su(H), Lag-1). CSL interacts with both transcriptional corepressor and coactivator proteins, functioning as both a repressor and activator, respectively. While Notch activation complexes are relatively well understood at the structural level, less is known about how CSL interacts with corepressors...
May 9, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28484120/microrna-99a-reduces-lipopolysaccharide-induced-oxidative-injury-by-activating-notch-pathway-in-h9c2-cells
#20
Ran Jing, Zhengming Zhou, Feng Kuang, Lei Huang, Chuanchang Li
microRNA-99a (miR-99a) is recently recognized as a key regulator in various cancers and cardiovascular diseases. In the present study, we sought to investigate the effects of miR-99a in rat cardiomyocyte H9c2 cells against oxidative injury induced by lipopolysaccharide (LPS).MTT assay, reactive oxygen species (ROS) assay, flow cytometry and lactate dehydrogenase (LDH) assay were respectively used to explore viability, ROS levels, apoptosis, and cell death in H9c2 cells. Quantitative PCR (qRT-PCR) was performed to confirm the expression of miR-99a...
May 8, 2017: International Heart Journal
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