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jak inhibitor colon cancer

Nicolas Granofszky, Michaela Lang, Vineeta Khare, Gerald Schmid, Theresa Scharl, Franziska Ferk, Kristine Jimenez, Siegfried Knasmüller, Christoph Campregher, Christoph Gasche
Microsatellite instability (MSI) is present in ulcerative colitis and colitis-associated colorectal cancers. Certain factors released by polymorphonuclear cells (PMN) may drive mucosal frameshift mutations resulting in MSI and cancer. Here, we applied a co-culture system with PMNs and colon epithelial cells to identify such culprit factors. Subjecting HCT116+chr3 and HCEC-1CT MSI-reporter cell lines harboring mono-, di- or tetranucleotide DNA repeats linked to EGFP to activated PMNs induced frameshift mutations within all repeats, as quantified by flow cytometry...
November 2, 2017: Carcinogenesis
Sung-Hoon Jung, Su-Min Kim, Choong-Eun Lee
Reactive oxygen species (ROS) participate in malignant progression of cancers including epithelial-mesenchymal transition (EMT). We have investigated the role of suppressors of cytokine signaling (SOCS)1 as an inhibitor of ROS-induced EMT using colon cancer cell lines transduced with SOCS1 and shSOCS1. Hydrogen peroxide treatment induced EMT features such as elevation of vimentin and Snail with a corresponding reduction of E-cadherin. The EMT markers are significantly decreased upon SOCS1 over-expression while increased under SOCS1 knock-down...
September 20, 2016: Oncotarget
Xiang Xue, Sadeesh K Ramakrishnan, Kevin Weisz, Daniel Triner, Liwei Xie, Durga Attili, Asha Pant, Balázs Győrffy, Mingkun Zhan, Christin Carter-Su, Karin M Hardiman, Thomas D Wang, Michael K Dame, James Varani, Dean Brenner, Eric R Fearon, Yatrik M Shah
Dietary iron intake and systemic iron balance are implicated in colorectal cancer (CRC) development, but the means by which iron contributes to CRC are unclear. Gene expression and functional studies demonstrated that the cellular iron importer, divalent metal transporter 1 (DMT1), is highly expressed in CRC through hypoxia-inducible factor 2α-dependent transcription. Colon-specific Dmt1 disruption resulted in a tumor-selective inhibitory effect of proliferation in mouse colon tumor models. Proteomic and genomic analyses identified an iron-regulated signaling axis mediated by cyclin-dependent kinase 1 (CDK1), JAK1, and STAT3 in CRC progression...
September 13, 2016: Cell Metabolism
Hai-Xia Peng, Wei-Qi Wu, Da-Ming Yang, Rong Jing, Ji Li, Feng-Li Zhou, Yun-Fei Jin, Sai-Yu Wang, Yi-Min Chu
OBJECTIVES: Colorectal cancer is one of the most common malignancies. Recent studies investigated that B7-H4 is highly expressed in various cancers. We aimed at exploring the effect of B7-H4 siRNA on proliferation, invasion, and migration of LOVO cells which expressed B7-H4 notably. DESIGN AND METHODS: Colon adenocarcinoma dataset was downloaded from The Cancer Genome Atlas. 35 colorectal cancer patients admitted to Shanghai Tongren Hospital were enrolled in this study...
2015: BioMed Research International
M Buchert, C J Burns, M Ernst
Various human malignancies are characterized by excessive activation of the Janus family of cytoplasmic tyrosine kinases (JAK) and their associated transcription factors STAT3 and STAT5. In the majority of solid tumors, this occurs in response to increased abundance of inflammatory cytokines in the tumor microenvironment prominently produced by infiltrating innate immune cells. Many of these cytokines share common receptor subunits and belong to the interleukin (IL)-6/IL-11, IL-10/IL-22 and IL-12/IL-23 families...
February 25, 2016: Oncogene
Kleiton Augusto Santos Silva, Jiangling Dong, Yanjun Dong, Yanlan Dong, Nestor Schor, David J Tweardy, Liping Zhang, William E Mitch
Cachexia occurs in patients with advanced cancers. Despite the adverse clinical impact of cancer-induced muscle wasting, pathways causing cachexia are controversial, and clinically reliable therapies are not available. A trigger of muscle protein loss is the Jak/Stat pathway, and indeed, we found that conditioned medium from C26 colon carcinoma (C26) or Lewis lung carcinoma cells activates Stat3 (p-Stat3) in C2C12 myotubes. We identified two proteolytic pathways that are activated in muscle by p-Stat3; one is activation of caspase-3, and the other is p-Stat3 to myostatin, MAFbx/Atrogin-1, and MuRF-1 via CAAT/enhancer-binding protein δ (C/EBPδ)...
April 24, 2015: Journal of Biological Chemistry
Michael Bordonaro, Eric Drago, Wafa Atamna, Darina L Lazarova
Mutations in the WNT/beta-catenin pathway are present in the majority of all sporadic colorectal cancers (CRCs), and histone deacetylase inhibitors induce apoptosis in CRC cells with such mutations. This apoptosis is counteracted by (1) the signaling heterogeneity of CRC cell populations, and (2) the survival pathways induced by mitogens secreted from apoptotic cells. The phenomena of signaling heterogeneity and apoptosis-induced survival constitute the immediate mechanisms of resistance to histone deacetylase inhibitors, and probably other chemotherapeutic agents...
2014: PloS One
Toby J Phesse, Michael Buchert, Emma Stuart, Dustin J Flanagan, Maree Faux, Shoukat Afshar-Sterle, Francesca Walker, Hui-Hua Zhang, Cameron J Nowell, Robert Jorissen, Chin Wee Tan, Yumiko Hirokawa, Moritz F Eissmann, Ashleigh R Poh, Jordane Malaterre, Helen B Pearson, David G Kirsch, Paolo Provero, Valeria Poli, Robert G Ramsay, Oliver Sieber, Antony W Burgess, Dennis Huszar, Elizabeth Vincan, Matthias Ernst
Most colon cancers arise from somatic mutations in the tumor suppressor gene APC (adenomatous polyposis coli), and these mutations cause constitutive activation of the Wnt-to-β-catenin pathway in the intestinal epithelium. Because Wnt-β-catenin signaling is required for homeostasis and regeneration of the adult intestinal epithelium, therapeutic targeting of this pathway is challenging. We found that genetic activation of the cytokine-stimulated pathway mediated by the receptor gp130, the associated Jak (Janus kinase) kinases, and the transcription factor Stat3 (signal transducer and activator of transcription 3) was required for intestinal regeneration in response to irradiation-induced damage in wild-type mice and for tumorigenesis in Apc-mutant mice...
September 30, 2014: Science Signaling
Maria-Ioanna Ellina, Panagiotis Bouris, Alexios J Aletras, Achilleas D Theocharis, Dimitris Kletsas, Nikos K Karamanos
BACKGROUND: ErbB receptors, EGFR and HER2, have been implicated in the development and progression of colon cancer. Several intracellular pathways are mediated upon activation of EGFR and/or HER2 by EGF. However, there are limited data regarding the EGF-mediated signaling affecting functional cell properties and the expression of extracellular matrix macromolecules implicated in cancer progression. METHODS: Functional assays, such as cell proliferation, transwell invasion assay and migration were performed to evaluate the impact of EGFR/HER2 in constitutive and EGF-treated Caco-2 cells...
August 2014: Biochimica et Biophysica Acta
Li Zhang, Yanxin Zheng, Hongzhu Deng, Lei Liang, Juan Peng
Aloperine (ALO) is a quinolizidine alkaloid extracted from the leaves of Sophora alopecuroides (S. alopecuroides) and possesses anti-inflammatory, anti-allergenic, antitumor, and antiviral effects. In this study, when compared with seven other types of alkaloids extracted from S. alopecuroides, ALO treatment produced the most potent effects against HCT116 colon cancer cell types. ALO inhibited proliferation and induced apoptosis in HCT116 cells in a dose- and time-dependent manner as detected by MTT, clonogenic survival, and flow cytometric assays...
June 2014: International Journal of Molecular Medicine
Emma Stuart, Michael Buchert, Tracy Putoczki, Stefan Thiem, Ryan Farid, Joachim Elzer, Dennis Huszar, Paul M Waring, Toby J Phesse, Matthias Ernst
Aberrant activation of the latent transcription factor STAT3 and its downstream targets is a common feature of epithelial-derived human cancers, including those of the gastrointestinal tract. Mouse models of gastrointestinal malignancy implicate Stat3 as a key mediator of inflammatory-driven tumorigenesis, in which its cytokine/gp130/Janus kinase (Jak)-dependent activation provides a functional link through which the microenvironment sustains tumor promotion. Although therapeutic targeting of STAT3 is highly desirable, such molecules are not available for immediate clinical assessment...
February 2014: Molecular Cancer Therapeutics
H J An, E K Choi, J S Kim, S W Hong, J H Moon, J S Shin, S H Ha, K P Kim, Y S Hong, J L Lee, E K Choi, J S Lee, D H Jin, T W Kim
Janus kinase (JAK) is one of the main upstream activators of signal transducers and activators of transcription (STAT) that are constitutively activated in various malignancies and are associated with cell growth, survival, and carcinogenesis. Here, we investigated the role of JAKs in colorectal cancer in order to develop effective therapeutic targets for INCB018424, which is the first JAK1/2 inhibitor to be approved by FDA. After examining the basal expression levels of phospho-JAK1 and phospho-JAK2, we measured the effects of INCB018424 on the phosphorylation of JAK1/2 using western blot analysis...
2014: Neoplasma
Sam Cross-Knorr, Shaolei Lu, Kimberly Perez, Sara Guevara, Kate Brilliant, Claudio Pisano, Peter J Quesenberry, Murray B Resnick, Devasis Chatterjee
BACKGROUND: A major obstacle in treating colorectal cancer (CRC) is the acquired resistance to chemotherapeutic agents. An important protein in the regulation of cancer cell death and clinical outcome is Raf kinase inhibitor protein (RKIP). In contrast, activated signal transducer and activator of transcription 3 (STAT3) is a protein that promotes tumor cell survival by inhibiting apoptosis and has an important role in cancer progression in many of cancer types. The aim of this study was to evaluate the regulation of RKIP and STAT3 after treatment with clinically relevant chemotherapeutic agents (camptothecin (CPT) and oxaliplatin (OXP)) and the cytokine interleukin-6 (IL-6) in HCT116 colon cancer cells as well as evaluate the association between RKIP and STAT3 with clinical outcome of Stage II colon cancer patients...
2013: BMC Cancer
Junaid Abdulghani, Joshua E Allen, David T Dicker, Yingqiu Yvette Liu, David Goldenberg, Charles D Smith, Robin Humphreys, Wafik S El-Deiry
BACKGROUND: Approximately half of tumor cell lines are resistant to the tumor-selective apoptotic effects of tumor necrosis factor-related apoptosis-inducing ligand (Apo22L/TRAIL). Previously, we showed that combining Apo2L/TRAIL with sorafenib, a multikinase inhibitor, results in dramatic efficacy in Apo2L/TRAIL-resistant tumor xenografts via inhibition of Mcl-1. Soluble Apo2L/TRAIL is capable of binding to several surface receptors, including the pro-apoptotic death receptors, DR4 and DR5, and decoy receptors, DcR1 and DcR2...
2013: PloS One
H J An, E K Choi, J S Kim, S W Hong, J H Moon, J S Shin, S H Ha, K P Kim, Y S Hong, J L Lee, E K Choi, J S Lee, D H Jin, T W Kim
Janus kinase (JAK) is one of the main upstream activators of signal transducers and activators of transcription (STAT) that are constitutively activated in various malignancies and are associated with cell growth, survival, and carcinogenesis. Here, we investigated the role of JAKs in colorectal cancer in order to develop effective therapeutic targets for INCB018424, which is the first JAK1/2 inhibitor to be approved by FDA. After examining the basal expression levels of phospho-JAK1 and phospho-JAK2, we measured the effects of INCB018424 on the phosphorylation of JAK1/2 using western blot analysis...
September 20, 2013: Neoplasma
Eric Drago, Michael Bordonaro, Seon Lee, Wafa Atamna, Darina L Lazarova
Diet is one of the major lifestyle factors affecting incidence of colorectal cancer (CC), and despite accumulating evidence that numerous diet-derived compounds modulate CC incidence, definitive dietary recommendations are not available. We propose a strategy that could facilitate the design of dietary supplements with CC-preventive properties. Thus, nutrient combinations that are a source of apoptosis-inducers and inhibitors of compensatory cell proliferation pathways (e.g., AKT signaling) may produce high levels of programmed death in CC cells...
2013: PloS One
Stefan Thiem, Thomas P Pierce, Michelle Palmieri, Tracy L Putoczki, Michael Buchert, Adele Preaudet, Ryan O Farid, Chris Love, Bruno Catimel, Zhengdeng Lei, Steve Rozen, Veena Gopalakrishnan, Fred Schaper, Michael Hallek, Alex Boussioutas, Patrick Tan, Andrew Jarnicki, Matthias Ernst
Gastrointestinal cancers are frequently associated with chronic inflammation and excessive secretion of IL-6 family cytokines, which promote tumorigenesis through persistent activation of the GP130/JAK/STAT3 pathway. Although tumor progression can be prevented by genetic ablation of Stat3 in mice, this transcription factor remains a challenging therapeutic target with a paucity of clinically approved inhibitors. Here, we uncovered parallel and excessive activation of mTOR complex 1 (mTORC1) alongside STAT3 in human intestinal-type gastric cancers (IGCs)...
February 2013: Journal of Clinical Investigation
Zhitu Zhu, Enze Li, Yangyang Liu, Yu Gao, Hongzhi Sun, Guangyou Ma, Zhenghua Wang, Xiaomei Liu, Qingjun Wang, Xiujuan Qu, Yunpeng Liu, Yunlong Yu
BACKGROUND: The purpose of the research is to investigate the roles of Jak-STAT3 signaling pathway in bufalin-induced apoptosis in colon cancer SW620 cells. METHODS: The inhibitory effects of bufalin on cell proliferation were determined by MTT (Methyl thiazolyltetrazolium) assay. The morphological changes of cells were measured by Wright-Giemsa staining. The cell cycle arrest and apoptosis were tested by flow cytometry analysis. Western Blot was used to determine the protein expression of the apoptosis inhibitors livin and caspase-3, the apoptosis-related proteins Bax and Bcl-2, as well as the key protein kinases in the Jak-stat3 signaling pathway, stat3 and p-stat3...
October 30, 2012: World Journal of Surgical Oncology
P Yue, X Zhang, D Paladino, B Sengupta, S Ahmad, R W Holloway, S B Ingersoll, J Turkson
We present evidence that the cisplatin-resistant human ovarian cancer lines, A2780S/CP1 (S/CP1), A2780S/CP3 (S/CP3) and A2780S/CP5 (S/CP5), derived by subjecting the sensitive A2780S ovarian cancer line to multiple rounds of cisplatin treatments followed by recovery and are resistant to 1, 3 and 5 μM cisplatin, respectively, have increased colony-forming ability and altered morphology that is consistent with enhanced motility, migration and invasiveness in vitro. The malignant phenotype progresses with increasing resistance and is associated with hyperactive epidermal growth factor receptor (EGFR)/extracellular signal-regulated kinase (Erk)1/2 and janus kinases (Jaks), aberrant signal transducer and activator of transcription (Stat) 3 activation promoted by EGFR and Jaks, and epithelial-mesenchymal transition (EMT) in vitro...
May 3, 2012: Oncogene
Kenneth Leslie, Sizhi P Gao, Marjan Berishaj, Katrina Podsypanina, Hao Ho, Lionel Ivashkiv, Jacqueline Bromberg
INTRODUCTION: Tyrosine phosphorylated signal transducer and activator of transcription 3 (pStat3) is present in numerous cancers and is required for mediating tumorigenesis. Autocrine and paracrine interleukin (IL)-6 signaling is the principal mechanism by which Stat3 is persistently phosphorylated in epithelial tumors including breast, lung, colon and gastric cancer. The Ras oncogene mediates cellular transformation without evidence of pStat3 in cultured cells. Recently, however non-tyrosine phosphorylated Stat3 was shown to have a transcriptional activating function, a role in mitochondrial function and to mediate cell migration...
2010: Breast Cancer Research: BCR
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