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c Src kinase and cancer

Chao Huang, Zhe Zhang, Lihan Chen, Hank W Lee, Marina K Ayrapetov, Ting C Zhao, Yimei Hao, Jinsong Gao, Chunzhang Yang, Gautam U Mehta, Zhengping Zhuang, Xiaoren Zhang, Guohong Hu, Y Eugene Chin
Post-translational modifications of mammalian c-Src N-terminal and C-terminal domains regulate distinct functions: myristoylation of G2 controls its cell membrane association and phosphorylation of Y419/Y527 controls its activation or inactivation, respectively. We provide evidence that Src-cell membrane association-dissociation and catalytic activation-inactivation are both regulated by acetylation. In EGF-treated cells, CREB binding protein (CBP) acetylated an N-terminal lysine cluster (K5, K7, and K9) of c-Src to promote dissociation from the cell membrane...
March 12, 2018: Cancer Research
Risa Akizuki, Ryohei Maruhashi, Hiroaki Eguchi, Kazuki Kitabatake, Mitsutoshi Tsukimoto, Takumi Furuta, Toshiyuki Matsunaga, Satoshi Endo, Akira Ikari
Chemotherapy resistance is a major problem in the treatment of cancer, but the underlying mechanisms are not fully understood. We found that the expression levels of claudin-1 (CLDN1) and 3, tight junctional proteins, are upregulated in cisplatin (CDDP)-resistant human lung adenocarcinoma A549 (A549R) cells. A549R cells showed cross-resistance to doxorubicin (DXR). Here, the expression mechanism and function of CLDN1 and 3 were examined. CLDN1 and 3 were mainly localized at tight junctions concomitant with zonula occludens (ZO)-1, a scaffolding protein, in A549 and A549R cells...
March 7, 2018: Biochimica et Biophysica Acta
Sara G Pollan, Fangjin Huang, Jamie M Sperger, Joshua M Lang, Colm Morrissey, Anne E Cress, C Y Chu, Neil A Bhowmick, Sungyong You, Michael R Freeman, Danislav S Spassov, Mark M Moasser, William G Carter, Shakti Ranjan Satapathy, Kavita Shah, Beatrice S Knudsen
Tumor metastasis depends on the dynamic regulation of cell adhesion through β1-integrin. The Cub-Domain Containing Protein-1, CDCP1, is a transmembrane glycoprotein which regulates cell adhesion. Overexpression and loss of CDCP1 have been observed in the same cancer types to promote metastatic progression. Here, we demonstrate reduced CDCP1 expression in high-grade, primary prostate cancers, circulating tumor cells and tumor metastases of patients with castrate-resistant prostate cancer. CDCP1 is expressed in epithelial and not mesenchymal cells, and its cell surface and mRNA expression declines upon stimulation with TGFβ1 and epithelial-to-mesenchymal transition...
March 7, 2018: Oncogene
Thomas C Beadnell, Kelsey W Nassar, Madison M Rose, Erin G Clark, Brian P Danysh, Marie-Claude Hofmann, Nikita Pozdeyev, Rebecca E Schweppe
Advanced stages of papillary and anaplastic thyroid cancer continue to be plagued by a dismal prognosis, which is a result of limited effective therapies for these cancers. Due to the high proportion of thyroid cancers harboring mutations in the MAPK pathway, the MAPK pathway has become a focal point for therapeutic intervention in thyroid cancer. Unfortunately, unlike melanoma, a similar responsiveness to MAPK pathway inhibition has yet to be observed in thyroid cancer patients. To address this issue, we have focused on targeting the non-receptor tyrosine kinase, Src, and we and others have demonstrated that targeting Src results in inhibition of growth, invasion, and migration both in vitro and in vivo, which can be enhanced through the combined inhibition of Src and the MAPK pathway...
February 28, 2018: Oncogenesis
Anna Chorzalska, Nagib Ahsan, R Shyama Prasad Rao, Karim Roder, Xiaoqing Yu, John Morgan, Alexander Tepper, Steven Hines, Peng Zhang, Diana O Treaba, Ting C Zhao, Adam J Olszewski, John Reagan, Olin Liang, Philip A Gruppuso, Patrycja M Dubielecka
The introduction of tyrosine kinase inhibitors (TKI) has transformed chronic myeloid leukemia (CML) into a chronic disease with long-term survival exceeding 85%. However, resistance of CML stem cells to TKI may contribute to the 50% relapse rate observed after TKI discontinuation in molecular remission. We previously described a model of resistance to imatinib mesylate (IM), in which K562 cells cultured in high concentrations of imatinib mesylate showed reduced Bcr-Abl1 protein and activity levels while maintaining proliferative potential...
February 27, 2018: Molecular Oncology
Priyanka Grover, Sritama Nath, Monica D Nye, Ru Zhou, Mohammad Ahmad, Pinku Mukherjee
Pancreatic Ductal Adenocarcinoma (PDA) has a mortality rate that nearly matches its incidence rate. Transforming Growth Factor Beta (TGF-β) is a cytokine with a dual role in tumor development switching from a tumor suppressor to a tumor promoter. There is limited knowledge of how TGF-β function switches during tumorigenesis. Mucin 1 (MUC1) is an aberrantly glycosylated, membrane-bound, glycoprotein that is overexpressed in >80% of PDA cases and is associated with poor prognosis. In PDA, MUC1 promotes tumor progression and metastasis via signaling through its cytoplasmic tail (MUC1-CT) and interacting with other oncogenic signaling molecules...
January 23, 2018: Oncotarget
Yazhuo Zhang, Mengfang Xia, Ke Jin, Shufei Wang, Hang Wei, Chunmei Fan, Yingfen Wu, Xiaoling Li, Xiayu Li, Guiyuan Li, Zhaoyang Zeng, Wei Xiong
c-Met is a receptor tyrosine kinase belonging to the MET (MNNG HOS transforming gene) family, and is expressed on the surfaces of various cells. Hepatocyte growth factor (HGF) is the ligand for this receptor. The binding of HGF to c-Met initiates a series of intracellular signals that mediate embryogenesis and wound healing in normal cells. However, in cancer cells, aberrant HGF/c-Met axis activation, which is closely related to c-Met gene mutations, overexpression, and amplification, promotes tumor development and progression by stimulating the PI3K/AKT, Ras/MAPK, JAK/STAT, SRC, Wnt/β-catenin, and other signaling pathways...
February 19, 2018: Molecular Cancer
Baohui Qi, Ying Yang, Huan He, Xupeng Yue, Yuting Zhou, Xing Zhou, Yuying Chen, Min Liu, Anmian Zhang, Fachang Wei
A total of 29 novel compounds bearing N1-(2-aryl-1, 3-thiazolidin-4-one)-N3-aryl ureas were designed, synthesized and evaluated for their biological activities. The structure-activity relationships (SARs) and binding modes of this series of compounds were clarified together. Compound 29b was identified possessing high potency against multi-tyrosine kinases including Ron, c-Met, c-Kit, KDR, Src and IGF-1R, etc. In vitro antiproliferation and cytotoxicity of compound 29b against A549 cancer cell line were confirmed by IncuCyte live-cell imaging...
January 27, 2018: European Journal of Medicinal Chemistry
Lazaro E Aira, Elodie Villa, Pascal Colosetti, Parvati Gamas, Laurie Signetti, Sandrine Obba, Emma Proics, Fabien Gautier, Béatrice Bailly-Maitre, Arnaud Jacquel, Guillaume Robert, Frédéric Luciano, Philippe P Juin, Jean-Ehrland Ricci, Patrick Auberger, Sandrine Marchetti
Phosphorylation of Ser/Thr residues is a well-established modulating mechanism of the pro-apoptotic function of the BH3-only protein Bim. However, nothing is known about the putative tyrosine phosphorylation of this Bcl-2 family member and its potential impact on Bim function and subsequent Bax/Bak-mediated cytochrome c release and apoptosis. As we have previously shown that the tyrosine kinase Lyn could behave as an anti-apoptotic molecule, we investigated whether this Src family member could directly regulate the pro-apoptotic function of Bim...
February 2, 2018: Oncogene
Aurelia Busca, Yulia Konarski, Niranjala Gajanayaka, Shifawn O'Hara, Jonathan Angel, Maya Kozlowski, Ashok Kumar
The inhibitors of apoptosis (IAP) proteins, initially described in the context of apoptosis regulation as promoting cell survival, have recently emerged as key regulators of innate immune signaling. As a result, downregulation of IAP via Smac mimetics (SMM) has both survival and immunoregulatory effects. IAPs modulate cytokine production in murine models either as a single agent or in response to LPS. However, the role of SMM and the involvement of IAPs in primary human cells and in particular macrophages with respect to cytokine production and innate immune responses remain largely unknown...
January 22, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
Natalia I Díaz-Valdivia, Claudia C Calderón, Jorge E Díaz, Lorena Lobos-González, Hugo Sepulveda, Rina J Ortíz, Samuel Martinez, Veronica Silva, Horacio J Maldonado, Patricio Silva, Sergio Wehinger, Verónica A Burzio, Vicente A Torres, Martín Montecino, Lisette Leyton, Andrew F G Quest
Expression of the scaffolding protein Caveolin-1 (CAV1) enhances migration and invasion of metastatic cancer cells. Yet, CAV1 also functions as a tumor suppressor in early stages of cancer, where expression is suppressed by epigenetic mechanisms. Thus, we sought to identify stimuli/mechanisms that revert epigenetic CAV1 silencing in cancer cells and evaluate how this affects their metastatic potential. We reasoned that restricted tissue availability of anti-neoplastic drugs during chemotherapy might expose cancer cells to sub-therapeutic concentrations, which activate signaling pathways and the expression of CAV1 to favor the acquisition of more aggressive traits...
December 19, 2017: Oncotarget
Qinglong Guo, Lu Lu, Yan Liao, Xiaoping Wang, Yi Zhang, Yicheng Liu, Shaoliang Huang, Haopeng Sun, Zhiyu Li, Li Zhao
SRC family kinase was documented to have vital roles in adjusting cancer cell malignant behaviors. To date, the role of c-Src, a member of SRC family kinase, in resistance to paclitaxel in human ovarian cancer cells under hypoxia has not been investigated. In the present study, we discovered that hypoxic environment suppressed paclitaxel-induced G2/M phase arrest and blockade of c-Src improved ovarian cancer cells' sensitivity to paclitaxel. FV-429, a derivative of natural flavonoid wogonin, could suppress gene expression and activation of c-Src, followed by deteriorated Stat3 nuclear translocation and its binding to HIF-1α, resulting in paclitaxel resistance reversal through G2/M arrest potentiation...
January 11, 2018: Cell Death & Disease
Liang Jiang, Zhihai Wang, Chuan Liu, Zhitao Gong, Yucheng Yang, Houyong Kang, Yanshi Li, Guohua Hu
Objectives: The aim of our study was to investigate the role of TrkB pathway in tumor occurrence and development for in order to provide theoretical basis to laryngeal cancer therapy. Materials and methods: Biological characteristics of the cells were studied by migration tests and colony forming assay. Gene and protein expression analysis was performed by RT-PCR or western blot. in vivo experiments were conducted in syngeneic BALB/c mice. Results: Significant changes in protein and gene expression, including higher expression level of TrkB, were found in cells and laryngeal cancer specimens...
December 12, 2017: Oncotarget
Kun-Yuan Chiu, Tzu-Hsiu Chen, Chi-Luan Wen, Jin-Mei Lai, Chi-Chih Cheng, Hsiang-Chun Liu, Shih-Lan Hsu, Yew-Min Tzeng
Antcin-H, a natural triterpene, is purified from a famous anticancer medicinal mushroom, Antrodia cinnamomea, in Taiwan. This study showed that antcin-H inhibited the growth of human renal carcinoma 786-0 cells; the IC50 value (for 48 h) was 170  μ M. Besides, the migration and invasion of 786-0 cells were suppressed by antcin-H under noncytotoxic concentrations (<100  μ M); these events were accompanied by inhibition of FAK and Src kinase activities, decrease of paxillin phosphorylation, impairment of lamellipodium formation, and upregulation of TIMPs and downregulation of MMPs, especially MMP-7 expression...
2017: Evidence-based Complementary and Alternative Medicine: ECAM
Levi Arnold, Jonathan Enders, Sufi Mary Thomas
Head and neck squamous cell carcinoma (HNSCC) is a highly morbid disease. Recent developments including Food and Drug Administration (FDA) approved molecular targeted agent's pembrolizumab and cetuximab show promise but did not improve the five-year survival which is currently less than 40%. The hepatocyte growth factor receptor; also known as mesenchymal-epithelial transition factor (c-Met) and its ligand hepatocyte growth factor (HGF) are overexpressed in head and neck squamous cell carcinoma (HNSCC); and regulates tumor progression and response to therapy...
December 12, 2017: Cancers
Daisong Wang, Chunye Liu, Jingqiang Wang, Yingying Jia, Xin Hu, Hai Jiang, Zhi-Ming Shao, Yi Arial Zeng
The protein C receptor (PROCR) has emerged as a stem cell marker in several normal tissues and has also been implicated in tumor progression. However, the functional role of PROCR and the signaling mechanisms downstream of PROCR remain poorly understood. Here, we dissected the PROCR signaling pathways in breast cancer cells. Combining protein array, knockdown, and overexpression methods, we found that PROCR concomitantly activates multiple pathways. We also noted that PROCR-dependent ERK and PI3k-Akt-mTOR signaling pathways proceed through Src kinase and transactivation of insulin-like growth factor 1 receptor (IGF-1R)...
January 26, 2018: Journal of Biological Chemistry
Jia-Sin Yang, Chiao-Wen Lin, Yi-Hsien Hsieh, Ming-Hsien Chien, Chun-Yi Chuang, Shun-Fa Yang
Oral cancer is a solid malignant tumor that is prone to occur following hypoxia. There are no clear studies showing a link between hypoxia and oral carcinogenesis. Carbonic anhydrase IX (CAIX), which is a hypoxia-induced transmembrane protein, is highly expressed in various types of human cancer. However, the effects of CAIX on the metastasis of human oral cancer cells and the underlying molecular mechanisms have not been clarified. In this study, we observed that CAIX overexpression increased the migratory and invasive abilities of SCC-9 and SAS cells...
October 10, 2017: Oncotarget
Ling Hui, Fang Wang
Calcium-and integrin-binding protein 1(CIB1),a member of calcium binding protein containing EF-hand domain,has been shown to bind a variety of signaling proteins. Interaction of CIB1 with its various binding partners provides valuable insight into potential mechanisms by which CIB1 may regulate diverse tumors characteristic biological process that range from adhesion,migration,cell survival,proliferation,and angiogenesis. CIB1 has also been implicated in both the increase and decrease of cell proliferation...
October 30, 2017: Zhongguo Yi Xue Ke Xue Yuan Xue Bao. Acta Academiae Medicinae Sinicae
Yunshu Lu, Yipeng Yang, Yan Liu, Yajuan Hao, Yijian Zhang, Yunping Hu, Lin Jiang, Yurong Gong, Kejin Wu, Yingbin Liu
C-terminal Src kinase (Csk)-binding protein (Cbp) is a ubiquitously expressed transmembrane adaptor protein which regulating Src family kinase (SFK) activities. Although SFKs are well known for their involvement in breast cancer, the function of Cbp in breast carcinogenesis upon the adipose-tumor microenvironment has not been investigated. Here, we reported that adipose-derived mesenchymal stem cells (ASCs) induced increased expression of Cbp accompanied by enhanced cell proliferation and chemotherapy resistance in breast cancer cell MCF-7/ADR...
December 16, 2017: Biochemical and Biophysical Research Communications
Donghwan Jeon, Hyungjoo Kim, Keesoo Nam, Sunhwa Oh, Seog-Ho Son, Incheol Shin
BACKGROUND/AIM: Silica nanoparticles (nano-SiO2) are widely used in many industrial areas and there is much controversy surrounding cytotoxic effects of such nanoparticles. In order to determine the toxicity and possible molecular mechanisms involved, we conducted several tests with two breast cancer cell lines, MDA-MB-231 and Hs578T. MATERIALS AND METHODS: After exposure to nano-SiO2, growth, apoptosis, motility of breast cancer cells were monitored. In addition, modulation of signal transduction induced by nano-SiO2 was detected through western blot analysis...
November 2017: Anticancer Research
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