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Syk pathway cancer

Kristel Kodar, Jacquie L Harper, Melanie J McConnell, Mattie S M Timmer, Bridget L Stocker
INTRODUCTION: Macrophages play a significant role in the progression of diseases, such as cancer, making them a target for immune-modulating agents. Trehalose dibehenate (TDB) is known to activate M1-like macrophages via Mincle, however, the effect of TDB on M2-like macrophages, which are found in the tumor microenvironment, has not been studied. METHODS: qRT-PCR, flow cytometry, cytokine ELISA, and Western Blotting were used to study the effect of TDB on GM-CSF and M-CSF/IL-4 derived bone marrow macrophages (BMMs) from C57BL/6 and Mincle(-/-) mice...
July 19, 2017: Immunity, Inflammation and Disease
Sulgi Yoo, Mi-Yeon Kim, Jae Youl Cho
Beauvericin (BEA), a cyclic hexadepsipeptide produced by the fungus Beauveria bassiana, is known to have anti-cancer, anti-inflammatory, and anti-microbial actions. However, how BEA suppresses macrophage-induced inflammatory responses has not been fully elucidated. In this study, we explored the anti-inflammatory properties of BEA and the underlying molecular mechanisms using lipopolysaccharide (LPS)-treated macrophage-like RAW264.7 cells. Levels of nitric oxide (NO), mRNA levels of transcription factors and the inflammatory genes inducible NO synthase (iNOS) and interleukin (IL)-1, and protein levels of activated intracellular signaling molecules were determined by Griess assay, semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), luciferase reporter gene assay, and immunoblotting analysis...
July 2017: Korean Journal of Physiology & Pharmacology
Chizu Tanikawa, Yao-Zhong Zhang, Ryuta Yamamoto, Yusuke Tsuda, Masami Tanaka, Yuki Funauchi, Jinichi Mori, Seiya Imoto, Rui Yamaguchi, Yusuke Nakamura, Satoru Miyano, Hidewaki Nakagawa, Koichi Matsuda
Although recent cancer genomics studies have identified a large number of genes that were mutated in human cancers, p53 remains as the most frequently mutated gene. To further elucidate the p53-signalling network, we performed transcriptome analysis on 24 tissues in p53(+/+) or p53(-/-) mice after whole-body X-ray irradiation. Here we found transactivation of a total of 3551 genes in one or more of the 24 tissues only in p53(+/+) mice, while 2576 genes were downregulated. p53 mRNA expression level in each tissue was significantly associated with the number of genes upregulated by irradiation...
June 2017: EBioMedicine
Terry King-Wing Ma, Stephen P McAdoo, Frederick Wai Keung Tam
Glomerulonephritis (GN) affects patients of all ages and is an important cause of morbidity and mortality. Non-selective immunosuppressive drugs have been used in immune-mediated GN but often result in systemic side effects and occasionally fatal infective complications. There is increasing evidence from both preclinical and clinical studies that abnormal activation of receptor and non-receptor tyrosine kinase signalling pathways are implicated in the pathogenesis of immune-mediated GN. Activation of spleen tyrosine kinase (SYK), Bruton's tyrosine kinase (BTK), platelet-derived growth factor receptor (PDGFR), epidermal growth factor receptor (EGFR) and discoidin domain receptor 1 (DDR1) have been demonstrated in anti-GBM disease...
January 1, 2017: Nephrology, Dialysis, Transplantation
Ga Bin Park, Yoon Hee Chung, Daejin Kim
The expression of different toll-like receptors (TLRs) on tumor cells has been associated with disease aggressiveness, treatment resistance, and poor prognosis. The phosphatidylinositol 3-kinase (PI3K)/AKT pathway is considered critical for cancer cell survival and proliferation. Thus, we investigated the effect of TLR-stimulated PI3K activation on the epithelial-to-mesenchymal transition (EMT) of primary (Caov-3) and metastatic (SK‑OV‑3) epithelial ovarian cancer cell lines in this study. TLR engagement with various ligands promoted the expression of class IA PI3K (p110α, p110β, and p110δ) and increased the expression of mesenchymal markers (N-cadherin, Slug, Vimentin, Snail, α-SMA, and TCF) in SK‑OV‑3 cells...
May 2017: Oncology Reports
Xiaodan Qin, Liang Lin, Li Cao, Xinwei Zhang, Xiao Song, Jie Hao, Yan Zhang, Risheng Wei, Xiaojun Huang, Jin Lu, Qing Ge
Reelin is an extracellular matrix protein that is crucial for neuron migration, adhesion, and positioning. We examined the expression of Reelin in a large cohort of multiple myeloma patients recorded in Gene Expression Omnibus (GEO) database and used over-expression and siRNA knockdown of Reelin to investigate the role of Reelin in myeloma cell growth. We find that Reelin expression is negatively associated with myeloma prognosis. Reelin promotes myeloma cell proliferation in vitro as well as in vivo. The Warburg effect, evidenced by increased glucose uptake and lactate production, is also enhanced in Reelin-expressing cells...
March 27, 2017: Scientific Reports
Lin Jie, Wang Miao, Ji Yang, Liu Le, Gao Pan, Li Chunjie
OBJECTIVE: This study explores the mechanism of cyclooxygenase-2 (COX-2) upregulation in oral cancers associated with macrophage by using molecular biology techniques and primary culture of murine macrophage. METHODS: Murine macrophage was induced by macrophage colony-stimulating factor (M-CSF) and Cal27 conditional medium (CM). Purity of the macrophage was detected through CD68 immunofluorescence staining. Inhibitors of spleen tyrosine kinase (Syk) and nuclear factor κB (NFκB) were used to inhibit these pathways...
October 1, 2016: Hua Xi Kou Qiang Yi Xue za Zhi, Huaxi Kouqiang Yixue Zazhi, West China Journal of Stomatology
Aurélien Naldi, Romain M Larive, Urszula Czerwinska, Serge Urbach, Philippe Montcourrier, Christian Roy, Jérôme Solassol, Gilles Freiss, Peter J Coopman, Ovidiu Radulescu
The ability to build in-depth cell signaling networks from vast experimental data is a key objective of computational biology. The spleen tyrosine kinase (Syk) protein, a well-characterized key player in immune cell signaling, was surprisingly first shown by our group to exhibit an onco-suppressive function in mammary epithelial cells and corroborated by many other studies, but the molecular mechanisms of this function remain largely unsolved. Based on existing proteomic data, we report here the generation of an interaction-based network of signaling pathways controlled by Syk in breast cancer cells...
March 2017: PLoS Computational Biology
Mika Shapiro, Yair Herishanu, Ben-Zion Katz, Nili Dezorella, Clare Sun, Sigi Kay, Aaron Polliack, Irit Avivi, Adrian Wiestner, Chava Perry
A novel therapeutic approach in cancer, attempting to stimulate host anti-tumor immunity, involves blocking of immune checkpoints. Lymphocyte activation gene 3 (LAG3) is an immune checkpoint receptor expressed on activated/exhausted T cells. When engaged by the major histocompatibility complex (MHC) class II molecules, LAG3 negatively regulates T-cell function, thereby contributing to tumor escape. Intriguingly, a soluble LAG3 variant activates both immune and malignant MHC class II-presenting cells. In the study herein, we examined the role of LAG3 in the pathogenesis of chronic lymphocytic leukemia, an MHC class II-presenting malignancy, and show that chronic lymphocytic leukemia cells express and secrete LAG3...
May 2017: Haematologica
Xihua Yue, Jing Ai, Yang Xu, Yi Chen, Min Huang, Xinying Yang, Bo Hu, Haotian Zhang, Changxi He, Xinrong Yang, Weiguo Tang, Xia Peng, Liwei Dong, Hongyang Wang, Jia Fan, Jian Ding, Meiyu Geng
Deregulation of the immune system is believed to contribute to cancer malignancy, which has led to recent therapeutic breakthroughs facilitating antitumor immunity. In a malignant setting, immunoglobulin receptors, which are fundamental components of the human immune system, fulfill paradoxical roles in cancer pathogenesis. This study describes a previously unrecognized pro-oncogenic function of polymeric immunoglobulin receptor (pIgR) in the promotion of cell transformation and proliferation. Mechanistically, pIgR overexpression is associated with YES proto-oncogene 1, Src family tyrosine kinase (Yes) activation, which is required for pIgR-induced oncogenic growth...
June 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Sang Jae Lee, Jang-Sik Choi, Byeong-Gu Han, Hyoun Sook Kim, Ho-Juhn Song, Jaekyoo Lee, Seungyoon Nam, Sung-Ho Goh, Jung-Ho Kim, Jong Sung Koh, Byung Il Lee
Spleen tyrosine kinase (SYK) is a cytosolic nonreceptor protein tyrosine kinase that mediates key signal transduction pathways following the activation of immune cell receptors. SYK regulates cellular events induced by the B-cell receptor and Fc receptors with high intrinsic activity. Furthermore, SYK has been regarded as an attractive target for the treatment of autoimmune diseases and cancers. Here, we report the crystal structures of SYK in complex with seven newly developed inhibitors (G206, G207, O178, O194, O259, O272, and O282) to provide structural insights into which substituents of the inhibitors and binding regions of SYK are essential for lead compound optimization...
October 2016: FEBS Journal
Eloy F Robles, Maria Mena-Varas, Laura Barrio, Sara V Merino-Cortes, Péter Balogh, Ming-Qing Du, Takashi Akasaka, Anton Parker, Sergio Roa, Carlos Panizo, Idoia Martin-Guerrero, Reiner Siebert, Victor Segura, Xabier Agirre, Laura Macri-Pellizeri, Beatriz Aldaz, Amaia Vilas-Zornoza, Shaowei Zhang, Sarah Moody, Maria Jose Calasanz, Thomas Tousseyn, Cyril Broccardo, Pierre Brousset, Elena Campos-Sanchez, Cesar Cobaleda, Isidro Sanchez-Garcia, Jose Luis Fernandez-Luna, Ricardo Garcia-Muñoz, Esther Pena, Beatriz Bellosillo, Antonio Salar, Maria Joao Baptista, Jesús Maria Hernandez-Rivas, Marcos Gonzalez, Maria Jose Terol, Joan Climent, Antonio Ferrandez, Xavier Sagaert, Ari M Melnick, Felipe Prosper, David G Oscier, Yolanda R Carrasco, Martin J S Dyer, Jose A Martinez-Climent
NKX2 homeobox family proteins have a role in cancer development. Here we show that NKX2-3 is overexpressed in tumour cells from a subset of patients with marginal-zone lymphomas, but not with other B-cell malignancies. While Nkx2-3-deficient mice exhibit the absence of marginal-zone B cells, transgenic mice with expression of NKX2-3 in B cells show marginal-zone expansion that leads to the development of tumours, faithfully recapitulating the principal clinical and biological features of human marginal-zone lymphomas...
June 14, 2016: Nature Communications
Shi Hyoung Kim, Jae Gwang Park, Yong Deog Hong, Eunji Kim, Kwang-Soo Baik, Deok Hyo Yoon, Sunggyu Kim, Mi-Nam Lee, Ho Sik Rho, Song Seok Shin, Jae Youl Cho
ETHNOPHARMACOLOGICAL RELEVANCE: Seed of Torreya nucifera (L.) Siebold & Zucc is used to treat several diseases in Asia. Reports document that T. nucifera has anti-cancer, anti-inflammatory, anti-oxidative activities. In spite of numerous findings on its pharmacological effects, the understanding of the molecular inhibitory mechanisms of the plant remains to be studied. Therefore, we aimed to explore in vitro anti-inflammatory mechanisms of ethyl acetate fraction (Tn-EE-BF) prepared from the seed of T...
July 21, 2016: Journal of Ethnopharmacology
Yinan Yao, Hequan Li, Junjun Chen, Weiyi Xu, Guangdie Yang, Zhang Bao, Dajing Xia, Guohua Lu, Shuwen Hu, Jianying Zhou
During infection, triggering receptor expressed on myeloid cells-2 (TREM-2) restrains dendritic cells (DCs) and macrophages (MΦs) phagocytosis, as well as reduces pro-inflammatory cytokines release through DNAX-activation protein 12 (DAP12) signaling. However, the role of TREM-2 signaling in cancer has never been elucidated. In the current study, we found that TREM-2 was up-regulated on peripheral blood monocytes in tumor-bearing host. More TREM-2+DCs were detected in the lung of 3LL tumor-bearing mice. On the other hand, the level of TREM-2 on pulmonary MΦs positively correlated with the pathological staging of lung cancer...
May 17, 2016: Oncotarget
Kiera Rycaj, Eun Jeong Cho, Xin Liu, Hsueh-Ping Chao, Bigang Liu, Qiuhui Li, Ashwini K Devkota, Dingxiao Zhang, Xin Chen, John Moore, Kevin N Dalby, Dean G Tang
We have recently demonstrated that the undifferentiated PSA-/lo prostate cancer (PCa) cell population harbors self-renewing long-term tumor-propagating cells that are refractory to castration, thus representing a therapeutic target. Our goals here are, by using the same lineage-tracing reporter system, to track the dynamic changes of PSA-/lo and PSA+ cells upon castration in vitro, investigate the molecular changes accompanying persistent castration, and develop large numbers of PSA-/lo PCa cells for drug screening...
March 22, 2016: Oncotarget
Lan Wang, Jie Yin, Xuefei Wang, Miaomiao Shao, Fangfang Duan, Weicheng Wu, Peike Peng, Jing Jin, Yue Tang, Yuanyuan Ruan, Yihong Sun, Jianxin Gu
BACKGROUND & AIMS: C-type lectin-like receptor 2 (CLEC2) is a transmembrane receptor expressed on platelets and several hematopoietic cells. CLEC2 regulates platelet aggregation and the immune response. We investigated its expression and function in normal and transformed gastric epithelial cells from human tissues. METHODS: We performed tissue microarray analyses of gastric carcinoma samples collected from 96 patients who underwent surgery at Zhongshan Hospital of Fudan University in Shanghai, China and performed real-time polymerase chain reaction assays from an independent group of 60 patients; matched nontumor gastric mucosa tissues were used as the control...
May 2016: Gastroenterology
Ga Bin Park, Yeong Seok Kim, Hyun-Kyung Lee, Jae Wook Yang, Daejin Kim, Dae Young Hur
Transcriptionally active p63 (TAp63) promotes cell cycle arrest, senescence, and apoptosis in several cancer cells. Migration inhibitory factor (MIF)/CD74 regulates B-cell survival through nuclear factor (NF)-κB-dependent TAp63 expression. In this study, we investigated how the level of TAp63 expression influences the induction of apoptosis in baicalein-treated EBV-transformed B cells. Baicalein induced the expression of TAp63 and apoptosis signal-regulating kinase 1 (ASK1), as well as cytotoxicity, by disrupting the mitochondrial membrane and inhibiting the activation of phosphoinositide 3-kinase (PI3K)/Akt and NF-κB...
January 2016: Molecular and Cellular Biochemistry
Rebecca L Goldstein, Shao Ning Yang, Tony Taldone, Betty Chang, John Gerecitano, Kojo Elenitoba-Johnson, Rita Shaknovich, Wayne Tam, John P Leonard, Gabriela Chiosis, Leandro Cerchietti, Ari Melnick
Rationally designed combinations of targeted therapies for refractory cancers, such as activated B cell-like diffuse large B cell lymphoma (ABC DLBCL), are likely required to achieve potent, durable responses. Here, we used a pharmacoproteomics approach to map the interactome of a tumor-enriched isoform of HSP90 (teHSP90). Specifically, we chemically precipitated teHSP90-client complexes from DLBCL cell lines with the small molecule PU-H71 and found that components of the proximal B cell receptor (BCR) signalosome were enriched within teHSP90 complexes...
November 3, 2015: Journal of Clinical Investigation
Ye F Tian, Haelee Ahn, Rebecca S Schneider, Shao Ning Yang, Lidia Roman-Gonzalez, Ari M Melnick, Leandro Cerchietti, Ankur Singh
Non-Hodgkin lymphomas are a heterogeneous group of lymphoproliferative disorders of B and T cell origin that are treated with chemotherapy drugs with variable success rate that has virtually not changed over decades. Although new classes of chemotherapy-free epigenetic and metabolic drugs have emerged, durable responses to these conventional and new therapies are achieved in a fraction of cancer patients, with many individuals experiencing resistance to the drugs. The paucity in our understanding of what regulates the drug resistance phenotype and establishing a predictive indicator is, in great part, due to the lack of adequate ex vivo lymphoma models to accurately study the effect of microenvironmental cues in which malignant B and T cell lymphoma cells arise and reside...
December 2015: Biomaterials
Qian Qiu, Chun Yang, Wei Xiong, Houda Tahiri, Mathieu Payeur, Rosanne Superstein, Anne-Sophie Carret, Patrick Hamel, Benjamin Ellezam, Bussières Martin, Mark Vezina, Przemyslaw Sapieha, Guoxiang Liu, Pierre Hardy
Retinoblastoma (Rb) is an aggressive childhood cancer of the developing retina. This disease is associated with epigenetic deregulation of several cancer pathways including upregulation of the proto-oncogene spleen tyrosine kinase (SYK). We have previously demonstrated that lymphocyte-derived microparticles (LMPs) possess strong cytotoxic effect on cancer cells. This report demonstrated that LMPs have potent pro-apoptotic properties on human Rb cells, which was associated with a strong reduction of SYK expression...
December 2015: Apoptosis: An International Journal on Programmed Cell Death
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