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https://www.readbyqxmd.com/read/28535002/hsa-mir-485-5p-reverses-epithelial-to-mesenchymal-transition-and-promotes-cisplatin-induced-cell-death-by-targeting-pak1-in-oral-tongue-squamous-cell-carcinoma
#1
Xiu-Juan Lin, Chang-Li He, Ting Sun, Xue-Jing Duan, Yi Sun, Shi-Jiang Xiong
Oral squamous cell carcinoma (OSCC) is currently a highly prevalent disease worldwide. Cisplatin (CDDP) is widely used for the chemotherapy of OSCC. Yet, the molecular mechanisms responsible for cisplatin resistance have not been fully elucidated. In this study, we showed that overexpression of p21 (RAC1) activated kinase 1 (PAK1) induced epithelial to mesenchymal transition (EMT) and significantly promoted the invasion and migration of oral squamous cell carcinoma SCC25 cells. Emerging evidence indicates a strong link between resistance to therapy and the induction of EMT in cancer...
May 16, 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/28534988/p21-activated-protein-kinase-1-induces-the-invasion-of-gastric-cancer-cells-through-c-jun-nh2-terminal-kinase-mediated-activation-of-matrix-metalloproteinase-2
#2
Liang-Hui Li, Guo-Yang Wu, Yi-Zhuo Lu, Xue-Hua Chen, Bing-Ya Liu, Min-Hua Zheng, Jian-Chun Cai
Gastric cancer (GC) is one of the most common malignancies worldwide. The prognosis of GC is poor, mostly due to widespread metastasis. p21-activated kinase 1 (Pak1), the best characterized member of an evolutionarily conserved family of serine/threonine kinases, plays an important role in the regulation of cell morphogenesis, motility, mitosis and angiogenesis. By qRT-PCR and Gelatin zymograph assay, we demonstrated in the present study that stable overexpression of Pak1 induced matrix metalloproteinase (MMP)-2 mRNA expression and activity in the human MKN45 GC cell line...
May 16, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28534510/targeting-group-i-p21-activated-kinases-to-control-malignant-peripheral-nerve-sheath-tumor-growth-and-metastasis
#3
G Semenova, D S Stepanova, C Dubyk, E Handorf, S M Deyev, A J Lazar, J Chernoff
Malignant peripheral nerve sheath tumors (MPNSTs) are devastating sarcomas for which no effective medical therapies are available. Over 50% of MPSNTs are associated with mutations in NF1 tumor suppressor gene, resulting in activation of Ras and its effectors, including the Raf/Mek/Erk and PI3K/Akt/mTORC1 signaling cascades, and also the WNT/β-catenin pathway. As Group I p21-activated kinases (Group I Paks, PAK1/2/3) have been shown to modulate Ras-driven oncogenesis, we asked if these enzymes might regulate signaling in MPNSTs...
May 22, 2017: Oncogene
https://www.readbyqxmd.com/read/28508421/subversion-of-host-kinases-a-key-network-in-cellular-signaling-hijacked-by-helicobacter-pylori-caga
#4
REVIEW
Nicole Tegtmeyer, Matthias Neddermann, Carmen Isabell Asche, Steffen Backert
Helicobacter pylori is a paradigm of persistent pathogens and major risk factor for developing severe diseases including adenocarcinoma in the human stomach. An important bacterial factor linked to gastric disease progression is the cag pathogenicity island-encoded type-IV secretion system (T4SS) effector protein CagA. Translocated CagA undergoes tyrosine phosphorylation at EPIYA-motifs and then activates or inactivates multiple host signaling proteins in a phosphorylation-dependent and phosphorylation-independent fashion...
May 15, 2017: Molecular Microbiology
https://www.readbyqxmd.com/read/28502042/tale-of-the-good-and-the-bad-cdk5-remodeling-of-the-actin-cytoskeleton-in-the-brain
#5
REVIEW
Kavita Shah, Sandra Rossie
Cdk5 kinase, a cyclin-dependent kinase family member, is a key regulator of cytoskeletal remodeling in the brain. Cdk5 is essential for brain development during embryogenesis. After birth, it is essential for numerous neuronal processes such as learning and memory formation, drug addiction, pain signaling, and long-term behavior changes, all of which rely on rapid alterations in the cytoskeleton. Cdk5 activity is deregulated in various brain disorders including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and ischemic stroke, resulting in profound remodeling of the neuronal cytoskeleton, loss of synapses, and ultimately neurodegeneration...
May 13, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28455144/identification-of-nck1-as-a-novel-downstream-effector-of-stat3-in-colorectal-cancer-metastasis-and-angiogenesis
#6
Fan Zhang, Yan-Xia Lu, Qing Chen, Hui-Mei Zou, Jian-Ming Zhang, Yu-Han Hu, Xiao-Min Li, Wen-Juan Zhang, Wei Zhang, Chun Lin, Xue-Nong Li
Signal transducer and activator of transcription 3 (STAT3) is known to activate targets associated with invasion, proliferation, and angiogenesis in a wide variety of cancers. The adaptor protein NCK1 is involved in cytoskeletal movement and was identified as a STAT3-associated target in human tumors. However, the underlying molecular mechanism associated with colorectal cancer (CRC) metastasis is not yet completely understood. In this study, we report a novel STAT3 to NCK1 signaling pathway in colorectal cancer (CRC)...
April 25, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28450949/genetic-variation-in-the-3-untranslated-region-of-pak1-influences-schizophrenia-susceptibility
#7
Juan Jiang, Jianxiong Long, Weijun Ling, Guifeng Huang, Li Su
The present study aimed to investigate the association of two polymorphisms (rs2844337 and rs11237200) in the P21 protein (cell division control protein 42/Rac)-activated kinase 1 gene with susceptibility to schizophrenia (SCZ) in Chinese Zhuang and Chinese Han populations. A total of 700 patients with SCZ and 700 healthy controls were recruited. Rs2844337 and rs11237200 polymorphisms were genotyped using Sequenom technology. A total of 591 patients completed the Positive and Negative Syndrome Scale (PANSS) assessment...
March 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/28442678/frondoside-a-from-sea-cucumber-and-nymphaeols-from-okinawa-propolis-natural-anti-cancer-agents-that-selectively-inhibit-pak1-in-vitro
#8
Binh Cao Quan Nguyen, Kazuki Yoshimura, Shigenori Kumazawa, Shinkichi Tawata, Hiroshi Maruta
A sulfated saponin called "Frondoside A" (FRA) from sea cucumber and ingredients from Okinawa propolis (OP) have been previously shown to suppress the PAK1-dependent growth of A549 lung cancer as well as pancreatic cancer cells. However, the precise molecular mechanism underlying their anti-cancer action still remains to be clarified. In this study, for the first time, we found that both FRA and OP directly inhibit PAK1 in vitro in a selective manner (far more effectively than two other oncogenic kinases, LIMK and AKT)...
April 24, 2017: Drug Discoveries & Therapeutics
https://www.readbyqxmd.com/read/28442677/1-2-3-triazolyl-esterization-of-pak1-blocking-propolis-ingredients-artepillin-c-arc-and-caffeic-acid-ca-for-boosting-their-anti-cancer-anti-pak1-activities-along-with-cell-permeability
#9
Hideaki Takahashi, Binh Cao Quan Nguyen, Yoshihiro Uto, Md Shahinozzaman, Shinkichi Tawata, Hiroshi Maruta
Artepillin C (ARC) and caffeic acid (CA) are among the major anti-cancer ingredients of propolis, and block the oncogenic/melanogenic/ageing kinase PAK1. However, mainly due to their COOH moiety, cell-permeability of these herbal compounds is rather limited. Thus, in this study, in an attempt to increase their cell-permeability without any significant loss of their water-solubility, we have esterized both ARC and CA with the water-soluble 1,2,3-triazolyl alcohol through Click Chemistry. We found that this esterization boosts the anti-cancer activity of ARC and CA by 100 and over 400 folds, respectively, against the PAK-dependent growth of A549 lung cells, but show no effect on the PAK1-independent growth of B16F10 melanoma cells...
April 24, 2017: Drug Discoveries & Therapeutics
https://www.readbyqxmd.com/read/28430160/subverting-host-cell-p21-activated-kinase-a-case-of-convergent-evolution-across-pathogens
#10
REVIEW
Simona John Von Freyend, Terry Kwok-Schuelein, Hans J Netter, Gholamreza Haqshenas, Jean-Philippe Semblat, Christian Doerig
Intracellular pathogens have evolved a wide range of strategies to not only escape from the immune systems of their hosts, but also to directly exploit a variety of host factors to facilitate the infection process. One such strategy is to subvert host cell signalling pathways to the advantage of the pathogen. Recent research has highlighted that the human serine/threonine kinase PAK, or p21-activated kinase, is a central component of host-pathogen interactions in many infection systems involving viruses, bacteria, and eukaryotic pathogens...
April 21, 2017: Pathogens
https://www.readbyqxmd.com/read/28423670/invasive-fusobacterium-nucleatum-activates-beta-catenin-signaling-in-colorectal-cancer-via-a-tlr4-p-pak1-cascade
#11
Yongyu Chen, Yan Peng, Jiahui Yu, Ting Chen, Yaxin Wu, Lei Shi, Qing Li, Jiao Wu, Xiangsheng Fu
The underlying mechanism of Fusobacterium nucleatum (Fn) in the carcinogenesis of colorectal cancer (CRC) is poorly understood. Here, we examined Fn abundance in CRC tissues, as well as β-catenin, TLR4 and PAK1 protein abundance in Fn positive and Fn negative CRCs. Furthermore, we isolated a strain of Fn (F01) from a CRC tissue and examined whether Fn (F01) infection of colon cancer cells activated β-catenin signaling via the TLR4/P-PAK1/P-β-catenin S675 cascade. Invasive Fn was abundant in 62.2% of CRC tissues...
May 9, 2017: Oncotarget
https://www.readbyqxmd.com/read/28423593/anti-cancer-effect-of-novel-pak1-inhibitor-via-induction-of-puma-mediated-cell-death-and-p21-mediated-cell-cycle-arrest
#12
Tae-Gyun Woo, Min-Ho Yoon, Shin-Deok Hong, Jiyun Choi, Nam-Chul Ha, Hokeun Sun, Bum-Joon Park
Hyper-activation of PAK1 (p21-activated kinase 1) is frequently observed in human cancer and speculated as a target of novel anti-tumor drug. In previous, we also showed that PAK1 is highly activated in the Smad4-deficient condition and suppresses PUMA (p53 upregulated modulator of apoptosis) through direct binding and phosphorylation. On the basis of this result, we have tried to find novel PAK1-PUMA binding inhibitors. Through ELISA-based blind chemical library screening, we isolated single compound, IPP-14 (IPP; Inhibitor of PAK1-PUMA), which selectively blocks the PAK1-PUMA binding and also suppresses cell proliferation via PUMA-dependent manner...
April 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28410221/discovery-and-characterization-of-small-molecule-rac1-inhibitors
#13
Jamie L Arnst, Ashley L Hein, Margaret A Taylor, Nick Y Palermo, Jacob I Contreras, Yogesh A Sonawane, Andrew O Wahl, Michel M Ouellette, Amarnath Natarajan, Ying Yan
Aberrant activation of Rho GTPase Rac1 has been observed in various tumor types, including pancreatic cancer. Rac1 activates multiple signaling pathways that lead to uncontrolled proliferation, invasion and metastasis. Thus, inhibition of Rac1 activity is a viable therapeutic strategy for proliferative disorders such as cancer. Here we identified small molecule inhibitors that target the nucleotide-binding site of Rac1 through in silico screening. Follow up in vitro studies demonstrated that two compounds blocked active Rac1 from binding to its effector PAK1...
May 23, 2017: Oncotarget
https://www.readbyqxmd.com/read/28408623/protein-kinase-d1-pkd1-phosphorylation-on-ser-203-by-type-i-p21-activated-kinase-pak-regulates-pkd1-localization
#14
Jen-Kuan Chang, Yang Ni, Liang Han, James Sinnett-Smith, Rodrigo Jacamo, Osvaldo Rey, Steven H Young, Enrique Rozengurt
While PKC-mediated phosphorylation of protein kinase D1 (PKD1) has been extensively characterized, little is known about PKD1 regulation by other upstream kinases. Here, we report that stimulation of epithelial or fibroblastic cells with G protein-coupled receptor (GPCR) agonists, including angiotensin II or bombesin induced rapid and persistent PKD1 phosphorylation at Ser(203), a highly conserved residue located within the PKD1 N-terminal domain. Exposure to PKD or PKC family inhibitors did not prevent PKD1 phosphorylation at Ser(203), indicating that it is not mediated by autophosphorylation...
April 13, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28407626/exogenous-mirna-146a-enhances-the-therapeutic-efficacy-of-human-mesenchymal-stem-cells-by-increasing-vascular-endothelial-growth-factor-secretion-in-the-ischemia-reperfusion-injured-heart
#15
Hyang-Hee Seo, Se-Yeon Lee, Chang Youn Lee, Ran Kim, Pilseog Kim, Sekyung Oh, Hojin Lee, Min Young Lee, Jongmin Kim, Lark Kyun Kim, Ki-Chul Hwang, Woochul Chang
Adult stem cells have been studied as a promising therapeutic modality for the functional restoration of the damaged heart. In the present study, a strategy for enhancing the angiogenic efficacy of human mesenchymal stem cells (hMSCs) using micro-RNA was examined. We investigated whether micro-RNA-146a (miR-146a) influences the secretion of vascular endothelial growth factor (VEGF) and angiogenesis of MSCs. Our data indicated that miR-146a-transfected hMSCs (hMSCmiR-146a) decreased the expression of neurofibromin 2, an inhibitor of p21-activated kinase-1 (PAK1)...
2017: Journal of Vascular Research
https://www.readbyqxmd.com/read/28393858/hili-destabilizes-microtubules-by-suppressing-phosphorylation-and-gigaxonin-mediated-degradation-of-tbcb
#16
Hao Tan, Hua Liao, Lianfang Zhao, Yilu Lu, Siyuan Jiang, Dachang Tao, Yunqiang Liu, Yongxin Ma
Human PIWIL2, aka HILI, is a member of PIWI protein family and overexpresses in various tumors. However, the underlying mechanisms of HILI in tumorigenesis remain largely unknown. TBCB has a critical role in regulating microtubule dynamics and is overexpressed in many cancers. Here we report that HILI inhibits Gigaxonin-mediated TBCB ubiquitination and degradation by interacting with TBCB, promoting the binding between HSP90 and TBCB, and suppressing the interaction between Gigaxonin and TBCB. Meanwhile, HILI can also reduce phosphorylation level of TBCB induced by PAK1...
April 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28373445/pi3k-catalytic-isoform-alteration-promotes-the-limk1-related-metastasis-through-the-pak1-or-rock1-2-activation-in-cigarette-smoke-exposed-ovarian-cancer-cells
#17
Ga Bin Park, Daejin Kim
AIM: To investigate the molecular mechanisms by which long-term exposure to cigarette smoke extract (CSE) contributes to ovarian cancer metastasis. MATERIALS AND METHODS: Western blot analysis for diverse p110 isoforms of phosphoinositide 3-kinase (PI3K)-related signaling pathway and epithelial-mesenchymal transition (EMT) markers was performed to analyze the underlying mechanisms. Migratory activity of CSE-exposed ovarian cancer cells was determined by transendothelial migration and invasion assay...
April 2017: Anticancer Research
https://www.readbyqxmd.com/read/28373299/integrated-genomic-analyses-reveal-frequent-tert-aberrations-in-acral-melanoma
#18
Winnie S Liang, William Hendricks, Jeffrey Kiefer, Jessica Schmidt, Shobana Sekar, John Carpten, David W Craig, Jonathan Adkins, Lori Cuyugan, Zarko Manojlovic, Rebecca F Halperin, Adrienne Helland, Sara Nasser, Christophe Legendre, Laurence H Hurley, Karthigayini Sivaprakasam, Douglas B Johnson, Holly Crandall, Klaus J Busam, Victoria Zismann, Valerie Deluca, Jeeyun Lee, Aleksandar Sekulic, Charlotte E Ariyan, Jeffrey Sosman, Jeffrey Trent
Genomic analyses of cutaneous melanoma (CM) have yielded biological and therapeutic insights, but understanding of non-ultraviolet (UV)-derived CMs remains limited. Deeper analysis of acral lentiginous melanoma (ALM), a rare sun-shielded melanoma subtype associated with worse survival than CM, is needed to delineate non-UV oncogenic mechanisms. We thus performed comprehensive genomic and transcriptomic analysis of 34 ALM patients. Unlike CM, somatic alterations were dominated by structural variation and absence of UV-derived mutation signatures...
April 2017: Genome Research
https://www.readbyqxmd.com/read/28365983/engineering-pak1-allosteric-switches
#19
Onur Dagliyan, Andrei V Karginov, Sho Yagishita, Madeline E Gale, Hui Wang, Celine DerMardirossian, Claire M Wells, Nikolay V Dokholyan, Haruo Kasai, Klaus M Hahn
P21-activated kinases (PAKs) are important regulators of cell motility and morphology. It has been challenging to interrogate their functions because cells adapt to genetic manipulation of PAK, and because inhibitors act on multiple PAK isoforms. Here we describe genetically encoded PAK1 analogues that can be selectively activated by the membrane-permeable small molecule rapamycin. An engineered domain inserted away from the active site responds to rapamycin to allosterically control activity of the PAK1 isoform...
April 6, 2017: ACS Synthetic Biology
https://www.readbyqxmd.com/read/28363850/di-n-butyl-phthalate-exposure-negatively-influences-structural-and-functional-neuroplasticity-via-rho-gtpase-signaling-pathways
#20
Yuemin Ding, Lingchao Lu, Chengkai Xuan, Jiajv Han, Shumin Ye, Tingting Cao, Weibo Chen, Aiqing Li, Xiong Zhang
Di-n-butyl phthalate (DBP) has been reported to cause disruptions in hippocampal plasticity, but its specific mechanism has not yet been ascertained. In this research, a mouse model of chronic DBP exposure was generated by intragastric administration of DBP (10, 50, or 250°mg/kg/d) for 5 weeks. Chronic exposure to high concentrations of DBP (250°mg/kg/d) induced a spatial learning deficit in the Morris water maze in male mice. By determining the activity of Rho-GTPase signaling pathways in the hippocampal tissues, we found that DBP exposure inhibited the activity of Rac1/PAK1/LIMK1 but activated RhoA/ROCK/LIMK2 signaling and eventually suppressed cofilin activity by phosphorylation...
March 28, 2017: Food and Chemical Toxicology
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