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Syk pathway cancer

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...
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
Tong Wu, Xudong Wang, Jing Li, Xiuzhen Song, Ying Wang, Yunfeng Wang, Lei Zhang, Ziyao Li, Jiawei Tian
Breast cancer is a highly heterogeneous disease that is clinically classified into several subtypes. Among these subtypes, basal-like breast cancer largely overlaps with triple-negative breast cancer (TNBC), and these two groups are generally studied together as a single entity. Differences in the molecular makeup of breast cancers can result in different treatment strategies and prognoses for patients with different breast cancer subtypes. Compared with other subtypes, basal-like and other ER+ breast cancer subtypes exhibit marked differences in etiologic factors, clinical characteristics and therapeutic potential...
2015: PloS One
Alexander X Cartagena-Rivera, Wen-Horng Wang, Robert L Geahlen, Arvind Raman
A longstanding goal in cellular mechanobiology has been to link dynamic biomolecular processes underpinning disease or morphogenesis to spatio-temporal changes in nanoscale mechanical properties such as viscoelasticity, surface tension, and adhesion. This requires the development of quantitative mechanical microscopy methods with high spatio-temporal resolution within a single cell. The Atomic Force Microscope (AFM) can map the heterogeneous mechanical properties of cells with high spatial resolution, however, the image acquisition time is 1-2 orders of magnitude longer than that required to study dynamic cellular processes...
2015: Scientific Reports
Yu Yu, Stephanie Gaillard, Jude M Phillip, Tai-Chung Huang, Sneha M Pinto, Nayara G Tessarollo, Zhen Zhang, Akhilesh Pandey, Denis Wirtz, Ayse Ayhan, Ben Davidson, Tian-Li Wang, Ie-Ming Shih
Resistance to chemotherapy represents a major obstacle for long-term remission, and effective strategies to overcome drug resistance would have significant clinical impact. We report that recurrent ovarian carcinomas after paclitaxel/carboplatin treatment have higher levels of spleen tyrosine kinase (SYK) and phospho-SYK. In vitro, paclitaxel-resistant cells expressed higher SYK, and the ratio of phospho-SYK/SYK positively associated with paclitaxel resistance in ovarian cancer cells. Inactivation of SYK by inhibitors or gene knockdown sensitized paclitaxel cytotoxicity in vitro and in vivo...
July 13, 2015: Cancer Cell
Yue Lu, Shuangfan Cai, Hongsheng Tan, Wenwei Fu, Hong Zhang, Hongxi Xu
Oblongifolin C (OC), a natural small molecule compound extracted from Garcinia yunnanensis Hu, has been previously shown to have anti-cancer effect, but the anti-allergic effect of OC has not yet been investigated. The aim of the present study is to determine the anti-allergic effect of OC on IgE/Ag-induced mouse bone marrow-derived mast cells (BMMCs) and on the passive systemic anaphylaxis (PSA) reaction in mice. OC clearly suppressed cyclooxygenase-2 (COX-2)-dependent prostaglandin D2 (PGD2) generation as well as leukotriene C4 (LTC4) generation and the degranulation reaction in IgE/Ag-stimulated BMMCs...
August 2015: Molecular and Cellular Biochemistry
Xian Li, Ju Hye Yang, Ye Jin, Fansi Jin, Dong-Young Kim, Jae-Hoon Chang, Jung-Ae Kim, Jong-Keun Son, Tae Chul Moon, Kun Ho Son, Hyeun Wook Chang
ETHNOPHARMACOLOGICAL RELEVANCE: 15,16-Dihydrotanshinone I (DHT-I), isolated from the dried root of Salvia miltiorrhiza Bung, which is traditionally used to treat cardiovascular and inflammatory diseases agent in Chinese medicine. DHT-I has been reported to have a broad range of biological activities, including antibacterial activity, and has been used to treat circulatory disorders, hepatitis, inflammation, cancer, and neurodegenerative diseases. AIM OF THE STUDY: The aim of this study was to evaluate the anti-allergic inflammatory effects of DHT-I on degranulation and on the generation of eicosanoids, such as, prostaglandin D2 (PGD2) and leukotriene C4 (LTC4), in IgE/Ag-stimulated bone marrow-derived mast cells (BMMCs)...
July 1, 2015: Journal of Ethnopharmacology
Javier A Garcia-Vilas, Miguel A Medina, Fabio R Melo, Gunnar Pejler, Gianni Garcia-Faroldi
Damnacanthal, an anthraquinone obtained from the noni fruit (Morinda citrifolia L.), has been described to possess anti-cancer and anti-inflammatory properties. Since mast cells are key players in various inflammatory conditions as well as in cancer, we considered the possibility that the biological actions of damnacanthal, at least partly, could be due to effects on mast cells. Many of the biological activities of mast cells are mediated by IgE receptor cross-linking, which results in degranulation with release of preformed granule mediators, as well as de novo synthesis and release of additional compounds...
May 2015: Molecular Immunology
Tatyana Isayeva, Jie Xu, Camille Ragin, Qian Dai, Tiffiny Cooper, William Carroll, Dan Dayan, Marilena Vered, Bruce Wenig, Eben Rosenthal, William Grizzle, Joshua Anderson, Christopher D Willey, Eddy S Yang, Margaret Brandwein-Gensler
A large body of evidence shows that p16(INK4a) overexpression predicts improved survival and increased radiosensitivity in HPV-mediated oropharyngeal squamous cell carcinomas.(OPSCC). Here we demonstrate that the presence of transcriptionally active HPV16 in oral cavity squamous cell carcinomas does not correlate with p16(INK4a) overexpression, enhanced local tumor immunity, or improved outcome. It is interesting that HPV-mediated oropharyngeal squamous cell carcinomas can be categorized as having a 'nonaggressive' invasion phenotype, whereas aggressive invasion phenotypes are more common in HPV-negative squamous cell carcinomas...
May 2015: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
Maria Isabella Sereni, Elisa Baldelli, Guido Gambara, Jianghong Deng, Laura Zanotti, Elisabetta Bandiera, Eliana Bignotti, Monica Ragnoli, Germana Tognon, Antonella Ravaggi, Francesco Meani, Maurizio Memo, Roberto Angioli, Lance A Liotta, Sergio L Pecorelli, Emanuel Petricoin, Mariaelena Pierobon
Epithelial ovarian carcinoma (EOC) is a deadly disease, with a 5-year survival of 30%. The aim of the study was to perform broad-scale protein signaling activation mapping to evaluate if EOC can be redefined based on activated protein signaling network architecture rather than histology. Tumor cells were isolated using laser capture microdissection (LCM) from 72 EOCs. Tumors were classified as serous (n = 38), endometrioid (n = 13), mixed (n = 8), clear cell (CCC; n = 7), and others (n = 6). LCM tumor cells were lysed and subjected to reverse-phase protein microarray to measure the expression/activation level of 117 protein drug targets...
January 2015: Proteomics
Haruki Horiguchi, Motoyoshi Endo, Yuji Miyamoto, Yasuo Sakamoto, Haruki Odagiri, Tetsuro Masuda, Tsuyoshi Kadomatsu, Hironori Tanoue, Ikuyo Motokawa, Kazutoyo Terada, Masaki Suimye Morioka, Ichiro Manabe, Hideo Baba, Yuichi Oike
Angiopoietin-like protein 2 (ANGPTL2) plays an important role in inflammatory carcinogenesis and tumor metastasis by activating tumor angiogenesis and tumor cell chemotaxis and invasiveness. However, it is unclear whether ANGPTL2 expression has an effect on tumor cell survival. Here, we explored that possibility by determining whether ANGPTL2 expression altered survival of human colorectal cancer cell lines treated with antineoplastic drugs. To do so, we generated SW480 cells expressing ANGPTL2 (SW480/ANGPTL2) and control (SW480/Ctrl) cells...
December 2014: Cancer Science
Greg Coffey, Andreas Betz, Francis DeGuzman, Yvonne Pak, Mayuko Inagaki, Dale C Baker, Stanley J Hollenbach, Anjali Pandey, Uma Sinha
The heterogeneity and severity of certain autoimmune diseases and B-cell malignancies warrant simultaneous targeting of multiple disease-relevant signaling pathways. Dual inhibition of spleen tyrosine kinase (SYK) and Janus kinase (JAK) represents such a strategy and may elicit several benefits relative to selective kinase inhibition, such as gaining control over a broader array of disease etiologies, reducing probability of selection for bypass disease mechanisms, and the potential that an overall lower level suppression of individual targets may be sufficient to modulate disease activity...
December 2014: Journal of Pharmacology and Experimental Therapeutics
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