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https://www.readbyqxmd.com/read/29760530/let-k-ras-activate-its-own-inhibitor
#1
Alexander V Statsyuk
No abstract text is available yet for this article.
May 14, 2018: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29758119/loss-of-protein-phosphatase-6-in-mouse-keratinocytes-enhances-k-ras-g12d-driven-tumor-promotion
#2
Koreyuki Kurosawa, Yui Inoue, Yoichiro Kakugawa, Yoji Yamashita, Kosuke Kanazawa, Kazuhiro Kishimoto, Miyuki Nomura, Yuki Momoi, Ikuro Sato, Natsuko Chiba, Mai Suzuki, Honami Ogoh, Hidekazu Yamada, Koh Miura, Toshio Watanabe, Nobuhiro Tanuma, Masahiro Tachi, Hiroshi Shima
Here, we address the function of protein phosphatase 6 (PP6) loss on K-ras-initiated tumorigenesis in keratinocytes. To do so, we developed tamoxifen-inducible double mutant (K-rasG12D -expressing and Ppp6c-deficient) mice in which K-rasG12D expression is driven by the cytokeratin 14 (K14) promoter. Doubly-mutant mice showed early onset tumor formation in lip, nipples, external genitalia, anus and palms, and had to be sacrificed by three weeks after induction by tamoxifen, while comparably-treated K-rasG12D -expressing mice did not...
May 14, 2018: Cancer Science
https://www.readbyqxmd.com/read/29757973/a-new-strategy-to-control-and-eradicate-undruggable-oncogenic-k-ras-driven-pancreatic-cancer-molecular-insights-and-core-principles-learned-from-developmental-and-evolutionary-biology
#3
REVIEW
Robert E Van Sciver, Michael P Lee, Caroline Dasom Lee, Alex C Lafever, Elizaveta Svyatova, Kevin Kanda, Amber L Colliver, Lauren L Siewertsz van Reesema, Angela M Tang-Tan, Vasilena Zheleva, Monicah N Bwayi, Minglei Bian, Rebecca L Schmidt, Lynn M Matrisian, Gloria M Petersen, Amy H Tang
Oncogenic K-RAS mutations are found in virtually all pancreatic cancers, making K-RAS one of the most targeted oncoproteins for drug development in cancer therapies. Despite intense research efforts over the past three decades, oncogenic K-RAS has remained largely "undruggable". Rather than targeting an upstream component of the RAS signaling pathway (i.e., EGFR/HER2) and/or the midstream effector kinases (i.e., RAF/MEK/ERK/PI3K/mTOR), we propose an alternative strategy to control oncogenic K-RAS signal by targeting its most downstream signaling module, Seven-In-Absentia Homolog (SIAH)...
May 14, 2018: Cancers
https://www.readbyqxmd.com/read/29757658/a-macropinocytosis-intensifying-albumin-domain-based-scfv-antibody-and-its-conjugate-directed-against-k-ras-mutant-pancreatic-cancer
#4
Xiaofei Wang, Weijin Sheng, Yangyang Wang, Liang Li, Yi Li, Shenghua Zhang, Xiujun Liu, Shuzhen Chen, Yongsu Zhen
Enhanced macropinocytosis has been found in K-Ras mutant pancreatic cancer cells and through which albumin can massively enter into the K-Ras driven cancer cells suggesting its role serving as micropinocytosis-intensifying drug delivery carrier. In the present study, a novel recombinant protein Fv-LDP-D3 and its reconstituted analogue Fv-LDP-D3-AE were designed and prepared. In which, Fv is the fragment of an anti-EGFR antibody, D3 is the domain III of HSA, LDP is the apoprotein of the antitumor antibiotic lidamycin (LDM), and AE is an extremely cytotoxic enediyne derived from LDM...
May 14, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29755843/fdg-pet-ct-suvmax-and-iaslc-ats-ers-histologic-classification-a-new-profile-of-lung-adenocarcinoma-with-prognostic-value
#5
Marina Suárez-Piñera, José Belda-Sanchis, Alvaro Taus, Albert Sánchez-Font, Antoni Mestre-Fusco, Marcel Jiménez, Lara Pijuan
Quantitative analysis of glucose consumption measured by maximum standardized uptake value (SUVmax) in lung adenocarcinoma (LA) remains in discussion and metabolic information provided by FDG-PET is not included in cancer staging. The first aim of this work was to evaluate the correlation between SUVmax and different histologic subtypes of LA. The second aim was to establish the correlation between SUVmax and TNM, genetic mutations and prognostic. Glucose consumption of primary tumor was quantified using SUVmax in 112 patients with histologically-confirmed LA...
2018: American Journal of Nuclear Medicine and Molecular Imaging
https://www.readbyqxmd.com/read/29755670/systemic-inflammatory-status-predict-the-outcome-of-k-ras-wt-metastatic-colorectal-cancer-patients-receiving-the-thymidylate-synthase-poly-epitope-peptide-anticancer-vaccine
#6
Pierpaolo Correale, Cirino Botta, Nicoletta Staropoli, Valerio Nardone, Pierpaolo Pastina, Cristina Ulivieri, Claudia Gandolfo, Tatiana Cosima Baldari, Stefano Lazzi, Domenico Ciliberto, Rocco Giannicola, Antonella Fioravanti, Antonio Giordano, Silvia Zappavigna, Michele Caraglia, Pierfrancesco Tassone, Luigi Pirtoli, Maria Grazia Cusi, Pierosandro Tagliaferri
TSPP is an anticancer poly-epitope peptide vaccine to thymidylate synthase, recently investigated in the multi-arm phase Ib TSPP/VAC1 trial. TSPP vaccination induced immune-biological effects and showed antitumor activity in metastatic colorectal cancer (mCRC) patients and other malignancies. Progression-free and overall survival of 41 mCRC patients enrolled in the study correlated with baseline levels of CEA, immune-inflammatory markers (neutrophil/lymphocyte ratio, CRP, ESR, LDH, ENA), IL-4 and with post-treatment change in p-ANCA and CD56dim CD16bright NKs ( p < 0...
April 17, 2018: Oncotarget
https://www.readbyqxmd.com/read/29742265/antiproliferative-effect-of-urolithin-a-the-ellagic-acid-derived-colonic-metabolite-on-hepatocellular-carcinoma-hepg2-2-15-cells-by-targeting-lin28a-let-7a-axis
#7
Zhenpeng Qiu, Junxuan Zhou, Cong Zhang, Ye Cheng, Junjie Hu, Guohua Zheng
An abnormality in the Lin28/let-7a axis is relevant to the progression of hepatitis B virus (HBV)-positive hepatocellular carcinoma (HCC), which could be a novel therapeutic target for this malignant tumor. The present study aimed to investigate the antiproliferative and anti-invasive effects of urolithin A in a stable full-length HBV gene integrated cell line HepG2.2.15 using CCK-8 and transwell assays. The RNA and protein expressions of targets were assessed by quantitative PCR and western blot, respectively...
2018: Brazilian Journal of Medical and Biological Research, Revista Brasileira de Pesquisas Médicas e Biológicas
https://www.readbyqxmd.com/read/29736383/analysis-of-kras-gene-from-induced-pancreatic-cancer-rats-administered-with-momordica-charantia-and-ocimum-ba-s-ilicum-leaf-extracts
#8
J B Minari, C A Okelola, N C Ugochukwu
Objective: To analyze K-ras gene from induced pancreatic cancer rats administered with Momordica charantia and Ocimum basilicum leaf extracts. Methods: Twenty-five (25) adult rats weighing between 90-120 g were divided into 5 groups namely RA, RB, RC, NC and PC, each group had 5 rats. The PC which served as the control was fed with normal fish meal and water ad libitum; the NC which is the negative control received 20 mg/ml/week of Nitrosamines only while other groups received different concentrations of aqueous extract of both M ...
April 2018: Journal of Traditional and Complementary Medicine
https://www.readbyqxmd.com/read/29736317/klf5-mediates-the-hyper-proliferative-phenotype-of-the-intestinal-epithelium-in-mice-with-intestine-specific-endogenous-k-ras-g12d-expression
#9
Mandayam O Nandan, Agnieszka B Bialkowska, Vincent W Yang
Oncogenic K-Ras activation is a common mutational event in colorectal cancer. We previously showed that transcription factor, Krüppel-like factor 5 (KLF5), contributes to intestinal polyposis in mice with K-Ras activation. At 14 months of age, Villin-Cre/LSL-K-RasG12D mice developed small intestinal and colonic hyperplastic polyps while LSL-K-RasG12D had none. The intestinal crypts of Villin-Cre/LSL-K-RasG12D mice contained a higher number of mitotic figures and increased crypt heights compared to controls...
2018: American Journal of Cancer Research
https://www.readbyqxmd.com/read/29735543/rassf1a-deficiency-enhances-ras-driven-lung-tumorigenesis
#10
M Lee Schmidt, Katharine R Hobbing, Howard Donninger, Geoffrey J Clark
Mutant K-RAS has been shown to have both tumor-promoting and -suppressing functions, and growing evidence suggests that the RASSF family of tumor suppressors can act as RAS apoptosis and senescence effectors. It has been hypothesized that inactivation of the RASSF1A tumor suppressor facilitates K-RAS-mediated transformation by uncoupling it from apoptotic pathways such as the Hippo pathway. In human lung tumors, combined activation of K-RAS and inactivation of RASSF1A is closely associated with the development of the most aggressive and worst prognosis tumors...
May 7, 2018: Cancer Research
https://www.readbyqxmd.com/read/29731918/mir-211-regulates-the-expression-of-rrm2-in-tumoral-metastasis-and-recurrence-in-colorectal-cancer-patients-with-a-k-ras-gene-mutation
#11
Chiu-Chun Chang, Chun-Che Lin, Chia-Hung Wang, Chi-Chou Huang, Tao-Wei Ke, Po-Li Wei, Ken-Tu Yeh, Kai-Cheng Hsu, Nan-Yung Hsu, Ya-Wen Cheng
Colorectal cancer (CRC) ranks as the third-leading cause of cancer-associated mortalities in Taiwan. The expression of ribonucleotide reductase M2 ( RRM2 ) and p53R2 is associated with tumoral malignancy and progression in several types of cancer. The aim of the present study was to determine the association of p53R2/RRM2 with the upstream expression of microRNA ( miR)-211 and the association of expression levels of p53, APC and k-ras with clinical outcomes in patients with CRC. The study consisted of 192 tumor tissue samples obtained from patients with CRC...
May 2018: Oncology Letters
https://www.readbyqxmd.com/read/29724718/the-autotaxin-lysophosphatidic-acid-axis-promotes-lung-carcinogenesis
#12
Christiana Magkrioti, Nikos Oikonomou, Eleanna Kaffe, Marios-Angelos Mouratis, Nikos Xylourgidis, Iliana Barbayianni, Petros Megadoukas, Vaggelis Harokopos, Christos Valavanis, Jerold Chun, Alexandra Kosma, Georgios T Stathopoulos, Evangelos Bouros, Demosthenes Bouros, Konstantinos N Syrigos, Vassilis Aidinis
Pathogenesis and progression of lung cancer (LC) are governed by complex interactions between the environment and host genetic susceptibility, which is further modulated by genetic and epigenetic changes. Autotaxin (ATX, ENPP2) is a secreted glycoprotein that catalyzes the extracellular production of lysophosphatidic acid (LPA), a growth-factor-like phospholipid which is further regulated by phospholipid phosphatases (PLPP). LPA's pleiotropic effects in almost all cell types are mediated through at least six, G-protein coupled LPA receptors (LPAR) that exhibit overlapping specificities, widespread distribution, and differential expression profiles...
May 3, 2018: Cancer Research
https://www.readbyqxmd.com/read/29721757/nmr-1-h-13-c-15-n-backbone-and-13-c-side-chain-resonance-assignment-of-the-g12c-mutant-of-human-k-ras-bound-to-gdp
#13
Alok K Sharma, Seung-Joo Lee, Alan C Rigby, Sharon A Townson
K-Ras is a key driver of oncogenesis, accounting for approximately 80% of Ras-driven human cancers. The small GTPase cycles between an inactive, GDP-bound and an active, GTP-bound state, regulated by guanine nucleotide exchange factors and GTPase activating proteins, respectively. Activated K-Ras regulates cell proliferation, differentiation and survival by signaling through several effector pathways, including Raf-MAPK. Oncogenic mutations that impair the GTPase activity of K-Ras result in a hyperactivated state, leading to uncontrolled cellular proliferation and tumorogenesis...
May 2, 2018: Biomolecular NMR Assignments
https://www.readbyqxmd.com/read/29720559/a-raf-competitive-k-ras-binder-can-fail-to-functionally-antagonize-signaling
#14
Monique J Kauke, Alison W Tisdale, Ryan L Kelly, Christian J Braun, Michael T Hemann, K Dane Wittrup
Mutated in approximately 30% of human cancers, Ras GTPases are the most common drivers of oncogenesis and render tumors unresponsive to many standard therapies. Despite decades of research, no drugs directly targeting Ras are currently available. We have previously characterized a small protein antagonist of K-Ras, R11.1.6, and demonstrated its direct competition with Raf for Ras binding. Here we evaluate the effects of R11.1.6 on Ras signaling and cellular proliferation in a panel of human cancer cell lines...
May 2, 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29717265/identification-of-a-met-eif4g1-translational-regulation-axis-that-controls-hif-1%C3%AE-levels-under-hypoxia
#15
Astrid A Glück, Eleonora Orlando, Dominic Leiser, Michaela Poliaková, Lluís Nisa, Aurélie Quintin, Jacopo Gavini, Deborah M Stroka, Sabina Berezowska, Lukas Bubendorf, Andree Blaukat, Daniel M Aebersold, Michaela Medová, Yitzhak Zimmer
Poor oxygenation is a common hallmark of solid cancers that strongly associates with aggressive tumor progression and treatment resistance. While a hypoxia-inducible factor 1α (HIF-1α)-associated transcriptional overexpression of the hepatocyte growth factor (HGF) receptor tyrosine kinase (RTK) MET has been previously documented, any regulation of the HIF-1α system through MET downstream signaling in hypoxic tumors has not been yet described. By using MET-driven in vitro as well as ex vivo tumor organotypic fresh tissue models we report that MET targeting results in depletion of HIF-1α and its various downstream targets...
May 2, 2018: Oncogene
https://www.readbyqxmd.com/read/29706533/k-ras-populates-conformational-states-differently-from-its-isoform-h-ras-and-oncogenic-mutant-k-rasg12d
#16
Jillian A Parker, Alicia Y Volmar, Spiro Pavlopoulos, Carla Mattos
Structures of wild-type K-Ras from crystals obtained in the presence of guanosine triphosphate (GTP) or its analogs have remained elusive. Of the K-Ras mutants, only K-RasG12D and K-RasQ61H are available in the PDB representing the activated form of the GTPase not in complex with other proteins. We present the crystal structure of wild-type K-Ras bound to the GTP analog GppCH2 p, with K-Ras in the state 1 conformation. Signatures of conformational states obtained by one-dimensional proton NMR confirm that K-Ras has a more substantial population of state 1 in solution than H-Ras, which predominantly favors state 2...
April 20, 2018: Structure
https://www.readbyqxmd.com/read/29704996/p53-and-k-ras-mutations-in-lung-tissues-and-sputum-samples-of-individuals-exposed-to-smoky-coal-emissions-in-xuan-wei-county-china
#17
Phouthone Keohavong, Qing Lan, Weimin Gao
Lung cancer mortality in Xuan Wei County (XWC) is among the highest in China. Lung cancer in XWC is associated with exposure, in poorly vented homes, to coal smoke containing high levels of polycyclic aromatic hydrocarbons (PAHs). We have previously investigated mutations in the p53 tumor suppressor gene and the K-ras oncogene in lung carcinomas and in sputum samples from individuals exposed to smoky coal emissions in XWC. This paper summarizes the results concerning p53 and K-ras mutations from these studies, in relation to mutations found in lung cancer patients not exposed to smoky coal emissions...
May 2018: Mutation Research
https://www.readbyqxmd.com/read/29693372/biosynthesis-of-the-15-membered-ring-depsipeptide-neoantimycin
#18
Will Skyrud, Joyce Liu, Divya Thankachan, Maria Cabrera, Ryan F Seipke, Wenjun Zhang
Antimycins are a family of natural products possessing outstanding biological activities and unique structures, which have intrigued chemists for over a half century. Of particular interest are the ring-expanded antimycins that show promising anti-cancer potential and whose biosynthesis remains uncharacterized. Specifically, neoantimycin and its analogs have been shown to be effective regulators of the oncogenic proteins GRP78/BiP and K-Ras. The neoantimycin structural skeleton is built on a 15-membered tetralactone ring containing one methyl, one hydroxy, one benzyl and three alkylmoieties, as well as an amide linkage to a conserved 3-formamidosalicylic acid moiety...
April 25, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/29676621/interleukin-17a-in-the-pathogenesis-of-lung-adenocarcinoma
#19
Zhen Lin, Christian Nguyen, Beibei Xu, Erik K Flemington, Gilbert F Morris
RATIONALE: Evidence has shown that inhaled lung carcinogens, such as tobacco smoke, silica, or asbestos, induce a T-helper cell type 17 inflammatory environment. Interleukin-17A (commonly and hereafter called IL-17) is the signature cytokine of T-helper cell type 17 inflammation. We have shown previously that IL-17 overexpression promotes growth of lung adenocarcinoma in transgenic mouse models. Our additional findings suggest that IL-17 suppresses the function of the p53 tumor suppressor protein in a mutant K-Ras-expressing lung tumor cell line...
April 2018: Annals of the American Thoracic Society
https://www.readbyqxmd.com/read/29670543/phosphoinositide-3-kinase-signaling-pathway-in-pancreatic-ductal-adenocarcinoma-progression-pathogenesis-and-therapeutics
#20
REVIEW
Divya Murthy, Kuldeep S Attri, Pankaj K Singh
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy characterized by its sudden manifestation, rapid progression, poor prognosis, and limited therapeutic options. Genetic alterations in key signaling pathways found in early pancreatic lesions are pivotal for the development and progression of pancreatic intraepithelial neoplastic lesions into invasive carcinomas. More than 90% of PDAC tumors harbor driver mutations in K-Ras that activate various downstream effector-signaling pathways, including the phosphoinositide-3-kinase (PI3K) pathway...
2018: Frontiers in Physiology
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