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https://www.readbyqxmd.com/read/28707808/cytotoxic-necrotizing-factor-1-promotes-prostate-cancer-progression-through-activating-the-cdc42-pak1-axis
#1
Yaxiu Guo, Zhisong Zhang, Huiting Wei, Jingyu Wang, Junqiang Lv, Kai Zhang, Evan T Keller, Zhi Yao, Quan Wang
Uropathogenic Escherichia coli (UPEC) is the leading cause of urinary tract infections and plays a role in prostatic carcinogenesis and prostate cancer (PCa) progression. However, the mechanisms through which UPEC promotes PCa development and progression are unclear. Cytotoxic necrotizing factor 1 (CNF1) is one of the most important UPEC toxins and its role in PCa progression has never been studied. We found that UPEC-secreted CNF1 promoted the migration and invasion of PCa cells and PCa metastasis. In vitro studies showed that CNF1 promotes pro-migratory and pro-invasive activity through entering PCa cells and activating Cdc42, which subsequently induced PAK1 phosphorylation and upregulation of MMP-9 expression...
July 14, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28707321/expansion-of-bcr-abl1-cells-requires-pak2-but-not-pak1
#2
Leo Edlinger, Angelika Berger-Becvar, Ingeborg Menzl, Gregor Hoermann, Georg Greiner, Eva Grundschober, Zsuzsanna Bago-Horvath, Wael Al-Zoughbi, Gerald Hoefler, Christine Brostjan, Lars Gille, Richard Moriggl, Andreas Spittler, Veronika Sexl, Andrea Hoelbl-Kovacic
The p21-activated kinases (PAKs) are key nodes in oncogenic signalling pathways controlling growth, survival, and motility of cancer cells. Their activity is increased in many human cancers and is associated with poor prognosis. To date, PAK deregulation has mainly been studied in solid tumours, where PAK1 and PAK4 are the main isoforms deregulated. We show that PAK1 and PAK2 are the critical isoforms in a BCR/ABL1(+) haematopoietic malignancy. In suspension, leukaemic cells deficient for PAK1 and PAK2 undergo apoptosis, while the loss of either protein is well tolerated...
July 14, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28692051/transcriptional-regulation-of-ataxia-telangiectasia-and-rad3-related-protein-by-activated-p21-activated-kinase-1-protects-keratinocytes-in-uv-b-induced-premalignant-skin-lesions
#3
S Beesetti, J Mavuluri, R P Surabhi, T M Oberyszyn, K Tober, R S Pitani, L D Joseph, G Venkatraman, S K Rayala
Sun-induced skin lesions, in particular actinic keratosis, are generally considered as premalignant skin lesions that can progress into squamous cell carcinoma (SCC) and invasive SCC if left untreated. Therefore, understanding the molecular mechanisms by which the ultraviolet-B (UV-B)-exposed cells are being protected and the signaling pathways that promote the progression of certain premalignant skin lesions to malignant lesions will permit us to prevent or cure skin cancers. In the current study, we found that phospho-p21-activated kinase-1 (Pak1) and Pak1 expression was high in clinical samples of sunlight-induced premalignant skin lesions assessed by immunohistochemistry...
July 10, 2017: Oncogene
https://www.readbyqxmd.com/read/28655771/p115-rhogef-activates-the-rac1-gtpase-signaling-cascade-in-mcp1-induced-vascular-smooth-muscle-cell-migration-and-proliferation
#4
Nikhlesh K Singh, Jagadeesh Janjanam, Gadiparthi N Rao
Although the involvement of Rho proteins in the pathogenesis of vascular diseases is well studied, little is known about the role of their upstream regulators, namely, the Rho guanine nucleotide exchange factors (RhoGEFs). Here, we sought to identify the RhoGEFs involved in monocyte chemotactic protein 1 (MCP1)-induced vascular wall remodeling. We found that among the RhoGEFs tested, MCP1 induced tyrosine phosphorylation of p115 RhoGEF but not of PDZ RhoGEF or LARG in human aortic smooth muscle cells (HASMCs)...
June 27, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28638464/overexpression-of-pak1-correlates-with-aberrant-expression-of-emt-markers-and-poor-prognosis-in-non-small-cell-lung-cancer
#5
Zhiying Yang, Heran Wang, Longzheng Xia, Linda Oyang, Yujuan Zhou, Baihua Zhang, Xiaoyan Chen, Xia Luo, Qianjin Liao, Jianping Liang
Objective: p21-activated kinases (PAKs) are serine/threonine protein kinases. PAK1 and epithelial-mesenchymal transition (EMT) are key therapeutic targets in cancer. The clinical significance of PAK1 and its potential association with EMT phenotype in non-small cell lung cancer (NSCLC) was investigated. Methods: Immunohistochemistry was used to detect the expression of PAK1, and mesenchymal and epithelial markers (vimentin, N-cadherin, and E-cadherin) in 186 cases of NSCLC tissues and 50 cases of tumor-adjacent normal tissues...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/28629331/depletion-of-p21-activated-kinase-1-up-regulates-the-immune-system-of-apc-%C3%A2-14-mice-and-inhibits-intestinal-tumorigenesis
#6
Nhi Huynh, Kai Wang, Mildred Yim, Chelsea J Dumesny, Mauro S Sandrin, Graham S Baldwin, Mehrdad Nikfarjam, Hong He
BACKGROUND: P21-activated kinase 1 (PAK1) stimulates growth and metastasis of colorectal cancer (CRC) through activation of multiple signalling pathways. Up-regulation of CRC stem cell markers by PAK1 also contributes to the resistance of CRC to 5-fluorouracil. The aim of this study was to investigate the effect of PAK1 depletion and inhibition on the immune system and on intestinal tumour formation in APC(∆14/+) mice. METHODS: The PAK1 KO APC(∆14/+) mice were generated by cross-breeding of PAK1 KO mice with APC(∆14/+) mice...
June 19, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28628382/unpaking-runx3-functions-both-sides-of-the-coin
#7
Arun Kumar, Sandhya Sundaram, Suresh K Rayala, Ganesh Venkatraman
Post translational modifications of RUNX3 have been shown to play an important role in directing RUNX3 functions. In this review we highlight the phosphorylation dependent functions of RUNX3 as regulated by PAK1 and its implications on tumorigenesis.
June 19, 2017: Small GTPases
https://www.readbyqxmd.com/read/28627240/quercetin-has-antimetastatic-effects-on-gastric-cancer-cells-via-the-interruption-of-upa-upar-function-by-modulating-nf-%C3%AE%C2%BAb-pkc-%C3%AE-erk1-2-and-ampk%C3%AE
#8
Hai Li, Chen Chen
Gastric cancer (GC) is a malignancy with few effective treatment options after metastasis occurs. Quercetin (Qu) intake has been associated with reduced incidence and slow development of GC, probably due to its anti-proliferative and apoptotic effects, but it is unclear whether Qu can inhibit the metastatic activity. The urokinase plasminogen activator (uPA)/uPA receptor (uPAR) system plays an important role in cancer metastasis. In this study, we measured both uPA activity and uPAR expression in GC and pericarcinous tissues, and we investigated the correlation between uPAR expression and the migratory and invasive activities of various GC cell lines...
March 1, 2017: Integrative Cancer Therapies
https://www.readbyqxmd.com/read/28596575/infectious-pancreatic-necrosis-virus-enters-chse-214-cells-via-macropinocytosis
#9
Jorge Levican, Camila Miranda-Cárdenas, Ricardo Soto-Rifo, Francisco Aguayo, Aldo Gaggero, Oscar León
Infectious pancreatic necrosis virus (IPNV) is a non-enveloped virus belonging to the Birnaviridae family. IPNV produces an acute disease in salmon fingerlings, with high mortality rates and persistent infection in survivors. Although there are reports of IPNV binding to various cells, the viral receptor and entry pathways remain unknown. The aim of this study was to determine the endocytic pathway that allows for IPNV entry. We observed that IPNV stimulated fluid uptake and virus particles co-localysed with the uptake marker dextran in intracellular compartments, suggesting a role for macropinocytosis in viral entry...
June 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28574147/the-pak1-signalling-pathway-in-cardiac-disease-from-mechanistic-study-to-therapeutic-exploration
#10
REVIEW
Yanwen Wang, Shunyao Wang, Ming Lei, Mark Boyett, Hoyee Tsui, Wei Liu, Xin Wang
p21-activated kinase 1 (Pak1) is a member of the highly conserved family of serine/threonine protein kinases regulated by Ras-related small G-proteins, Cdc42/Rac1. It has been previously demonstrated to be involved in cardiac protection. Based on recent studies, this review assembles an overview of the role of Pak1 in cardiac diseases including disrupted Ca(2+) homoeostasis related cardiac arrhythmias, β-adrenergic stress and pressure overload-induced hypertrophy, and ischemia/reperfusion injury. These findings demonstrate the importance of Pak1 regulation through phosphorylation and transcriptional modification of hypertrophy and/or arrhythmia-related genes...
June 2, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28556956/prognostic-value-of-p21-activated-kinase-4-in-resected-pancreatic-cancer
#11
Sehhoon Park, Jin Won Kim, Haeryoung Kim, Ji-Won Kim, Yu Jung Kim, Keun-Wook Lee, Jee Hyun Kim, Jai Hwan Kim, Jin-Hyeok Hwang, Young Rok Choi, Jai Young Cho, Yoo-Seok Yoon, Ho-Seong Han
Resectable pancreatic cancer has a high recurrence rate after curative surgery. Biomarkers are needed for distinguishing patients who may benefit from curative resection. In this study, we sought to analyze the prognostic value of p21-activated kinase 1 (PAK1), p21-activated kinase 4 (PAK4), human equilibrative nucleoside transporter 1 (hENT1), and thymidylate synthase (TS) in surgically resected pancreatic ductal adenocarcinomas. A total of 160 pancreatic cancer patients who underwent surgery with curative intent were retrospectively reviewed...
May 30, 2017: APMIS: Acta Pathologica, Microbiologica, et Immunologica Scandinavica
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
#12
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...
July 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
#13
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
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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