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Suyong Lin, Shaoqin Chen, Zhihua Chen, Qibao Dai, Chunlin Ke
PURPOSE: The purpose of this study was to investigate the relation between X-ray irradiation and epithelial-mesenchymal transition (EMT), as well as the potential mechanisms of X-ray-induced EMT in SW480 colorectal cancer (CRC) cells. METHODS: It is well known that EMT plays a critical role in invasive and metastatic of colorectal cancer progression. However, the possible role of X-ray irradiation on EMT in colorectal cancer is widely disputed and its potential mechanisms are unclear...
November 2017: Journal of B.U.ON.: Official Journal of the Balkan Union of Oncology
Chimno Ihuoma Nnadi, Meredith L Jenkins, Daniel R Gentile, Leslie A Bateman, Daniel Zaidman, Trent E Balius, Daniel K Nomura, John E Burke, Kevan M Shokat, Nir London
The success of targeted covalent inhibitors in the global pharmaceutical industry has led to a resurgence of covalent drug discovery. However, covalent inhibitor design for flexible binding sites remains a difficult task due to lack of methodological development. Here, we compared covalent docking to empirical electrophile screening, against the highly dynamic target K-RasG12C. While the overall hit-rate of both methods was comparable, we were able to rapidly progress a docking hit to a potent irreversible covalent inhibitor that modifies the inactive, GDP-bound state of K-RasG12C...
January 10, 2018: Journal of Chemical Information and Modeling
Hideaki Ando, Katsuhiro Kawaai, Benjamin Bonneau, Katsuhiko Mikoshiba
The calcium ion (Ca2+) is a ubiquitous intracellular signaling molecule that regulates diverse physiological and pathological processes, including cancer. Increasing evidence indicates that oncogenes and tumor suppressors regulate the Ca2+ transport systems. Inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs) are IP3-activated Ca2+ release channels located on the endoplasmic reticulum (ER). They play pivotal roles in the regulation of cell death and survival by controlling Ca2+ transfer from the ER to mitochondria through mitochondria-associated ER membranes (MAMs)...
December 20, 2017: Advances in Biological Regulation
Melanie Kripp, Nicole Prasnikar, Ursula Vehling-Kaiser, Julia Quidde, Salah-Eddin Al-Batran, Alexander Stein, Kai Neben, Carla Verena Hannig, Hans Werner Tessen, Tanja Trarbach, Axel Hinke, Ralf-Dieter Hofheinz
Background: Dermatologic toxicities, especially akne-like skin rash, are the most common side-effects associated with anti-epidermal growth factor receptor (EGFR) therapy. Preemptive treatment with oral tetracyclines is recommended as a standard. Topical prophylactic options have thus far not been compared to tetracyclines. In the current study, we sought to establish an alternative topical treatment. Patients and methods: In this multicentre, randomized, open-label phase II study patients with (K)Ras-wildtype colorectal cancer receiving panitumumab were randomized (1:1) to receive either doxycycline 100 mg b...
December 1, 2017: Oncotarget
Long Ge, Bei Pan, Fujian Song, Jichun Ma, Dena Zeraatkar, Jianguo Zhou, Jinhui Tian
INTRODUCTION: Surgical resection is the only curative treatment for patients with resectable pancreatic cancer. Unfortunately, 80%-85% of patients present with locally advanced or metastatic unresectable pancreatic cancer at the time of diagnosis. Detection of pancreatic cancer at early stages remains a great challenge due to lack of accurate detection tests. Recommendations in existing clinical practice guidelines on early diagnosis of pancreatic cancer are inconsistent and based on limited evidence...
December 26, 2017: BMJ Open
Madoka Naemura, Masahide Kuroki, Toshiyuki Tsunoda, Nagisa Arikawa, Yuuga Sawata, Senji Shirasawa, Yojiro Kotake
BACKGROUND/AIM: OPA-interacting protein 5 antisense transcript 1 (OIP5-AS1) is a long noncoding RNA located on human chromosome 15q15.1 and transcribed in the opposite direction to OIP5. Here, we report that OIP5-AS1 is involved in regulating cell proliferation. MATERIALS AND METHODS: HeLa cells were transfected with OIP5-AS1-targeting siRNA oligonucleotides and anti-sense oligonucleotides. The cells were harvested 72 h after transfection and subjected to quantitative reverse transcription-polymerase chain reaction (qRT-PCR), and cell-cycle and apoptosis analysis...
January 2018: Anticancer Research
Xin Li, Zhirong Zhang, Yili Fu, Jinbai Miao, Bin Hu
In recent years, based on low-dose computed tomography (CT) scan developed for physical examination, the number of synchronous multiple primary lung cancer (SMPLC) has gradually increased. The research showed the morbidity of SMPLC up to 0.2%-8%. The current diagnostic criteria of SMPLC is Martini-Melamed criteria. SMPLC: (1) Tumours should be located distantly and separately; (2) Histological types: Different histology; If same histology, they should be located at different segment, lobe or lung and originated from carcinoma insitu...
December 20, 2017: Zhongguo Fei Ai za Zhi, Chinese Journal of Lung Cancer
Ruth Nussinov, Chung-Jung Tsai, Hyunbum Jang
How do Ras isoforms attain oncogenic specificity at the membrane? Oncogenic KRas, HRas, and NRas (K-Ras, H-Ras, and N-Ras) differentially populate distinct cancers. How they selectively activate effectors and why is KRas4B the most prevalent are highly significant questions. Here, we consider determinants that may bias isoform-specific effector activation and signaling at the membrane. We merge functional data with a conformational view to provide mechanistic insight. Cell-specific expression levels, pathway cross-talk, and distinct interactions are the key, but conformational trends can modulate selectivity...
December 22, 2017: Cancer Research
Paolo Bossi, Marco Siano, Cristiana Bergamini, Maria Cossu Rocca, Andrea P Sponghini, Marco Giannoccaro, Luca Tonella, Alessandro Paoli, Edoardo Marchesi, Federica Perrone, Silvana Pilotti, Laura D Locati, Silvana Canevari, Lisa Licitra, Loris De Cecco
Prediction of benefit from combined chemotherapy and the antiepidermal growth factor receptor cetuximab is a not yet solved question in head and neck squamous cell carcinoma (HNSCC). In a selected series of 14 long progression-free survival (PFS) and 26 short PFS patients by whole gene and microRNA expression analysis, we developed a model potentially predictive of cetuximab sensitivity. To better decipher the "omics" profile of our patients, we detected transcript fusions by RNA-seq through a Pan-Cancer panel targeting 1385 cancer genes...
2017: Disease Markers
Xiaoguang Wang, Jingshuai Wang, Fei Chen, Zhengxiang Zhong, Lifeng Qi
The present study aimed to investigate the feasibility and effectiveness of detecting K-ras mutation by using magnetic nanoparticles in fecal samples of patients with pancreatic cancer at different stages. The novel methodology of K-ras mutation detection was compared to the existing methodology of cancer antigen (CA)19-9 examination. Patients with pancreatic cancer (n=88), pancreatic benign diseases who displayed chronic pancreatitis (n=35), pancreatic mucinous cyst neoplasms (n=10) and pancreatic serous cyst (n=9) admitted to the Department of Surgery, Jiaxing Second Hospital were enrolled in the present study...
January 2018: Experimental and Therapeutic Medicine
Daniela Volonte, Avani R Vyas, Chen Chen, Sanja Dacic, Laura P Stabile, Brenda F Kurland, Shira R Abberbock, Timothy F Burns, James M Herman, Yuanpu Peter Di, Ferruccio Galbiati
Oncogene-induced senescence (OIS) is considered a powerful tumor suppressor mechanism. Caveolin-1 acts as a scaffolding protein to functionally regulate signaling molecules. We demonstrate that a lack of caveolin-1 expression inhibits oncogenic K-Ras (K-RasG12V)-induced premature senescence in mouse embryonic fibroblasts (MEFs) and normal human bronchial epithelial (NHBE) cells. Oncogenic K-Ras induces senescence by limiting the detoxification function of MTH1. We find that K-RasG12V promotes the interaction of caveolin-1 with MTH1, which results in inhibition of MTH1 activity...
December 15, 2017: Journal of Biological Chemistry
Long Wang, Yifan Zhao, Yajie Xiong, Wenjuan Wang, Yao Fei, Caihong Tan, Zhongqin Liang
K-ras mutation is involved in cancer progression including invasion and migration, but the underlying mechanism is not yet clear. Cathepsin L is a lysosomal cysteine protease and has recently been associated with invasion and migration in human cancers when it is overexpressed. Our recent studies have shown that ionizing radiation (IR) enhanced expression of cathepsin L and increased invasion and migration of tumor cells, but the molecular mechanism is still unclear. In the present study, the effects of K-ras mutation and IR induced invasion and migration of lung cancer as well as the underlying mechanisms were investigated both in vitro and in vivo...
December 12, 2017: Experimental Cell Research
Hua Jin, Qing Li, Fenghao Cao, Shu-Nan Wang, Ren-Tao Wang, Yun Wang, Qun-You Tan, Cheng-Run Li, Hua Zou, Dong Wang, Cheng-Xiong Xu
Dysregulated miRNAs play important role in K-ras mutation or smoking caused lung tumorigenesis. Here, we investigate the role and mechanism of miR-124 in K-ras mutation or smoking-caused lung tumorigenesis and evaluate the therapeutic potential of miR-124 agomiR in K-ras mutation or smoking-caused lung cancer treatment. Our data show that smoking suppresses miR-124 expression, and decreased miR-124 expression is inversely correlated with the p-Akt level and predicts poor overall survival in non-small-cell lung cancer (NSCLC) patients...
December 15, 2017: Molecular Therapy. Nucleic Acids
Shin Hamada, Keiko Taguchi, Atsushi Masamune, Masayuki Yamamoto, Tooru Shimosegawa
The Keap1-Nrf2 system contributes to the maintenance of homeostasis by regulating oxidative stress responses in normal tissues and organs, and is exploited in various cancers for proliferation, survival and acquisition of therapy resistance. Pancreatic cancer remains one of the intractable cancers, despite the improved clinical outcomes of other types of cancer, due to its invasive and refractory nature to therapeutic intervention. The current study aimed to clarify the contribution of Nrf2 to pancreatic carcinogenesis using a pancreas-specific mutant K-ras and p53 (KPC) mouse model...
June 1, 2017: Carcinogenesis
Hui Jing, Xiaoyu Zhang, Stephanie A Wisner, Xiao Chen, Nicole A Spiegelman, Maurine E Linder, Hening Lin
Ras proteins play vital roles in numerous biological processes and Ras mutations are found in many human tumors. Understanding how Ras proteins are regulated is important for elucidating cell signaling pathways and identifying new targets for treating human diseases. Here we report that one of the K-Ras splice variants, K-Ras4a, is subject to lysine fatty acylation, a previously under-studied protein post-translational modification. Sirtuin 2 (SIRT2), one of the mammalian nicotinamide adenine dinucleotide (NAD)-dependent lysine deacylases, catalyzes the removal of fatty acylation from K-Ras4a...
December 14, 2017: ELife
Yong Zhou, John F Hancock
Ras proteins must localize to the plasma membrane (PM) for biological function. The membrane anchor of the K-Ras4B isoform comprises a farnesylated and methylated C-terminal cysteine together with an adjacent hexa-lysine polybasic domain (PBD). Traditionally, polybasic sequences have been thought to interact electrostatically with negatively charged membranes showing no specificity for anionic lipid head groups. By contrast we recently showed that the K-Ras membrane anchor actually exhibits a very high degree of specificity for phosphatidylserine (PtdSer)...
December 14, 2017: Small GTPases
Yong Zhou, Priyanka Prakash, Alemayehu A Gorfe, John F Hancock
The primary site of Ras signal transduction is the plasma membrane (PM). On the PM, the ubiquitously expressed Ras isoforms, H-, N-, and K-Ras, spatially segregate to nonoverlapping nanometer-sized domains, called nanoclusters, with further lateral segregation into nonoverlapping guanosine triphosphate (GTP)-bound and guanosine diphosphate (GDP)-bound nanoclusters. Effector binding and activation is restricted to GTP nanoclusters, rendering the underlying assembly mechanism essential to Ras signaling. Ras nanoclusters have distinct lipid compositions as a result of lipid-sorting specificity encoded in each Ras carboxy-terminal membrane anchor...
December 11, 2017: Cold Spring Harbor Perspectives in Medicine
Hamid A Bakshi, Faruck Lukmanul Hakkim, Smitha Sam, Farideh Javid
Crocus sativus and its bioactive constituent crocin are well known for anti-tumor potential in different models. However, the efficacy of crocin on in-vivo melanoma metastasis is not yet reported. In this study, melanoma metastatic model was developed by tail vein injection of B16F-10 cells in to C57BL/6 mice. Metastatic mice treated with two different doses of crocin (250 and 500 µg/kg of bodyweight) for 10 days and parameters such as lung metastasis inhibition, mean survival time, lung hydroxyproline, uronic acid and hexosamine levels were analyzed after 21 days of treatment...
November 1, 2017: Journal of Biomedical Research
Laurence Booth, Jane L Roberts, Andrew Poklepovic, John Kirkwood, Cindy Sander, Francesca Avogadri-Connors, Richard E Cutler, Alshad S Lalani, Paul Dent
The FDA approved irreversible inhibitor of ERBB1/2/4, neratinib, was recently shown to rapidly down-regulate the expression of ERBB1/2/4 as well as the levels of c-MET and mutant K-RAS via autophagic degradation. In the present studies, in a dose-dependent fashion, neratinib reduced the expression levels of mutant K-RAS or of mutant N-RAS, which was augmented in an additive to greater than additive fashion by the HDAC inhibitors sodium valproate and AR42. Neratinib could reduce PDGFRα levels in GBM cells, that was enhanced by sodium valproate...
December 8, 2017: Cancer Biology & Therapy
Shenyuan Xu, Brian N Long, Gabriel H Boris, Anqi Chen, Shuisong Ni, Michael A Kennedy
K-Ras, a molecular switch that regulates cell growth, apoptosis and metabolism, is activated when it undergoes a conformation change upon binding GTP and is deactivated following the hydrolysis of GTP to GDP. Hydrolysis of GTP in water is accelerated by coordination to K-Ras, where GTP adopts a high-energy conformation approaching the transition state. The G12A mutation reduces intrinsic K-Ras GTP hydrolysis by an unexplained mechanism. Here, crystal structures of G12A K-Ras in complex with GDP, GTP, GTPγS and GppNHp, and of Q61A K-Ras in complex with GDP, are reported...
December 1, 2017: Acta Crystallographica. Section D, Structural Biology
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