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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
#1
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
#2
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
#3
REVIEW
Simona John Von Freyend, Terry Kwok-Schuelein, Hans 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
#4
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...
March 7, 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
#5
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
#6
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...
March 29, 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
#7
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
#8
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)...
April 14, 2017: Journal of Vascular Research
https://www.readbyqxmd.com/read/28393858/hili-destabilizes-microtubules-by-suppressing-phosphorylation-and-gigaxonin-mediated-degradation-of-tbcb
#9
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
#10
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
#11
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
#12
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
#13
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
https://www.readbyqxmd.com/read/28360125/cellular-levels-of-growth-factor-receptor-bound-protein-2-grb2-and-cytoskeleton-stability-are-correlated-in-a-neurodegenerative-scenario
#14
Piyali Majumder, Kasturi Roy, Brijesh Kumar Singh, Nihar Ranjan Jana, Debashis Mukhopadhyay
Alzheimer's Disease (AD) manifests neuronal loss. On the premises of Grb2 overexpression in AD mouse brain and brain tissues of AD patients, our study primarily focuses on the stability of cytoskeletal proteins in the context of degenerative AD like conditions. Two predominant molecular features of AD, extracellular accumulation of Aβ oligomers and intracellular elevation of AICD levels, have been used to closely inspect the series of signaling events. In their presence, multiple signaling pathways involving ROCK and PAK1 proteins lead to disassembly of the cytoskeleton and Grb2 partially counterbalances the cytoskeletal loss...
March 30, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28320610/carbon-monoxide-releasing-molecule-401-suppresses-polymorphonuclear-leukocyte-migratory-potential-by-modulating-f-actin-dynamics
#15
Ken Inoue, Eric K Patterson, Alfredo Capretta, Abdel R Lawendy, Douglas D Fraser, Gediminas Cepinskas
Carbon monoxide-releasing molecules (CORMs) suppress inflammation by reducing polymorphonuclear leukocyte (PMN) recruitment to the affected organs. We investigated modulation of PMN-endothelial cell adhesive interactions by water-soluble CORM-401 using an experimental model of endotoxemia in vitro. Human umbilical vein endothelial cells grown on laminar-flow perfusion channels were stimulated with 1 μg/mL lipopolysaccharide for 6 hours and perfused with 100 μmol/L CORM-401 (or inactive compound iCORM-401)-pretreated PMN for 5 minutes in the presence of 1...
March 17, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28301299/differential-role-for-pak1-and-pak4-during-the-invadopodia-lifecycle
#16
Nicole S Nicholas, Aikaterini Pipili, Michaela S Lesjak, Claire M Wells
PAK1 and PAK4 are members of the p-21 activated kinase family of serine/threonine kinases. PAK1 has previously been implicated in both the formation and disassembly of invasive cell protrusions, termed invadopodia. We recently reported a novel role for PAK4 during invadopodia maturation and confirmed a specific role for PAK1 in invadopodia formation; findings we will review here. Moreover, we found that PAK4 induction of maturation is delivered via interaction with the RhoA regulator PDZRho-GEF. We can now reveal that loss of PAK4 expression leads to changes in invadopodia dynamics...
March 16, 2017: Small GTPases
https://www.readbyqxmd.com/read/28288786/p21-activated-kinase-4-regulates-hif-1%C3%AE-translation-in-cancer-cells
#17
Hyunju Kim, Dustin J Woo, So Yeon Kim, Eun Gyeong Yang
The p21-activated kinases (Paks) interact with Rac/Cdc42 GTPases to regulate the actin cytoskeleton as well as various signaling pathways. Although activation of Paks in many human cancers is known to mediate cancer progression, the role of Pak proteins in hypoxia is poorly understood. In this study, we found that both Pak1 and Pak4 are highly expressed in HeLa cervical cancer cells, but only Pak4 knockdown attenuates expression of hypoxia-inducible factor-1α (HIF-1α) in hypoxia. We further discovered that Pak4 regulates HIF-1α translation via the Akt-mTOR-4E-BP1 pathway under hypoxic conditions...
April 29, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28288135/targeting-lyn-regulates-snail-family-shuttling-and-inhibits-metastasis
#18
D Thaper, S Vahid, K M Nip, I Moskalev, X Shan, S Frees, M E Roberts, K Ketola, K W Harder, C Gregory-Evans, J L Bishop, A Zoubeidi
The acquisition of an invasive phenotype by epithelial cells occurs through a loss of cellular adhesion and polarity, heralding a multistep process that leads to metastatic dissemination. Since its characterization in 1995, epithelial-mesenchymal transition (EMT) has been closely linked to the metastatic process. As a defining aspect of EMT, loss of cell adhesion through downregulation of E-cadherin is carried out by several transcriptional repressors; key among them the SNAI family of transcription factors...
March 13, 2017: Oncogene
https://www.readbyqxmd.com/read/28287395/p27-kip1-promotes-invadopodia-turnover-and-invasion-through-the-regulation-of-the-pak1-cortactin-pathway
#19
Pauline Jeannot, Ada Nowosad, Renaud T Perchey, Caroline Callot, Evangeline Bennana, Takanori Katsube, Patrick Mayeux, François Guillonneau, Stéphane Manenti, Arnaud Besson
p27(Kip1) (p27) is a cyclin-CDK inhibitor and negative regulator of cell proliferation. p27 also controls other cellular processes including migration and cytoplasmic p27 can act as an oncogene. Furthermore, cytoplasmic p27 promotes invasion and metastasis, in part by promoting epithelial to mesenchymal transition. Herein, we find that p27 promotes cell invasion by binding to and regulating the activity of Cortactin, a critical regulator of invadopodia formation. p27 localizes to invadopodia and limits their number and activity...
March 13, 2017: ELife
https://www.readbyqxmd.com/read/28278510/autocrine-vegf-and-il-8-promote-migration-via-src-vav2-rac1-pak1-signaling-in-human-umbilical-vein-endothelial-cells
#20
Li Ju, Zhiwen Zhou, Bo Jiang, Yue Lou, Xirong Guo
BACKGROUND/AIMS: Pro-angiogenic factors VEGF and IL-8 play a major role in modulating the migratory potential of endothelial cells. The goal of this study was to investigate the effect of autocrine VEGF and IL-8 in the form of self-conditioned medium (CM) on human umbilical vein endothelial cells (HUVECs). METHODS: Enzyme-linked immunosorbent assay (ELISA) examined the automatic secretion of VEGF and IL-8 protein by HUVECs. Western blot, small interfering RNA (siRNA), pulldown and Transwell assays were used to explore the role and the mechanism of autocrine VEGF and IL-8 in migration of HUVECs...
March 9, 2017: Cellular Physiology and Biochemistry
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