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https://www.readbyqxmd.com/read/28530791/farnesyltransferase-mediated-delivery-of-a-covalent-inhibitor-overcomes-alternative-prenylation-to-mislocalize-k-ras
#1
Christopher J Novotny, Gregory L Hamilton, Frank McCormick, Kevan Shokat
Mutationally activated Ras is one of the most common oncogenic drivers found across all malignancies, and its selective inhibition has long been a goal in both pharma and academia. One of the oldest and most validated methods to inhibit overactive Ras signaling is by interfering with its post-translational processing and subsequent cellular localization. Previous attempts to target Ras processing led to the development of farnesyltransferase inhibitors, which can inhibit H-Ras localization but not K-Ras due to its ability to bypass farnesyltransterase inhibition though alternative prenylation by geranylgeranyltransferase...
May 22, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28500307/alox5-exhibits-anti-tumor-and-drug-sensitizing-effects-in-mll-rearranged-leukemia
#2
Yungui Wang, Jennifer R Skibbe, Chao Hu, Lei Dong, Kyle Ferchen, Rui Su, Chenying Li, Hao Huang, Hengyou Weng, Huilin Huang, Xi Qin, Jie Jin, Jianjun Chen, Xi Jiang
MLL-rearranged acute myeloid leukemia (AML) remains a fatal disease with a high rate of relapse and therapeutic failure due to chemotherapy resistance. In analysis of our Affymetrix microarray profiling and chromatin immunoprecipitation (ChIP) assays, we found that ALOX5 is especially down-regulated in MLL-rearranged AML, via transcription repression mediated by Polycomb repressive complex 2 (PRC2). Colony forming/replating and bone marrow transplantation (BMT) assays showed that Alox5 exhibited a moderate anti-tumor effect both in vitro and in vivo...
May 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28498561/distinct-dynamics-and-interaction-patterns-in-h-and-k-ras-oncogenic-p-loop-mutants
#3
Abdallah Sayyed-Ahmad, Priyanka Prakash, Alemayehu A Gorfe
Despite years of study the structural or dynamical basis for the differential reactivity and oncogenicity of Ras isoforms and mutants remains unclear. In this study, we investigated the effects of amino acid variations on the structure and dynamics of wild type and oncogenic mutants G12D, G12V and G13D of H- and K-Ras proteins. Based on data from µs-scale molecular dynamics simulations, we show that the overall structure of the proteins remains similar but there are crucial differences in dynamics and interaction networks...
May 12, 2017: Proteins
https://www.readbyqxmd.com/read/28496334/erratum-lead-identification-for-the-k-ras-protein-virtual-screening-and-combinatorial-fragment-based-approaches-corrigendum
#4
(no author information available yet)
[This corrects the article on p. 2575 in vol. 9, PMID: 27217775.].
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28472779/anti-tumor-efficacy-of-theliatinib-in-esophageal-cancer-patient-derived-xenografts-models-with-epidermal-growth-factor-receptor-egfr-overexpression-and-gene-amplification
#5
Yongxin Ren, Jianming Zheng, Shiming Fan, Linfang Wang, Min Cheng, Dongxia Shi, Wei Zhang, Renxiang Tang, Ying Yu, Longxian Jiao, Jun Ni, Haibin Yang, Huaqing Cai, Fang Yin, Yunxin Chen, Feng Zhou, Weihan Zhang, Weiguo Qing, Weiguo Su
Targeted therapy is not yet approved for esophageal cancer (EC). In this study, we first evaluated EGFR gene and protein expression in 70 Chinese EC patient tumor samples collected during surgery. We then established 23 patient-derived EC xenograft (PDECX) models and assessed the efficacy of theliatinib, a potent and highly selective EGFR inhibitor currently in Phase I clinical study, in 9 PDECX models exhibiting various EGFR expression levels. Immunohistochemical analysis showed that 50 patient tumor samples (71...
April 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/28471392/taking-a-bad-turn-compromised-dna-damage-response-in-leukemia
#6
REVIEW
Nadine Nilles, Birthe Fahrenkrog
Genomic integrity is of outmost importance for the survival at the cellular and the organismal level and key to human health. To ensure the integrity of their DNA, cells have evolved maintenance programs collectively known as the DNA damage response. Particularly challenging for genome integrity are DNA double-strand breaks (DSB) and defects in their repair are often associated with human disease, including leukemia. Defective DSB repair may not only be disease-causing, but further contribute to poor treatment outcome and poor prognosis in leukemia...
May 4, 2017: Cells
https://www.readbyqxmd.com/read/28468801/%C3%AE-np63%C3%AE-is-a-common-inhibitory-target-in-oncogenic-pi3k-ras-her2-induced-cell-motility-and-tumor-metastasis
#7
Linshan Hu, Shan Liang, Hu Chen, Tao Lv, Junfeng Wu, Deshi Chen, Min Wu, Shengnan Sun, Haibo Zhang, Han You, Hongbin Ji, Yujun Zhang, Johann Bergholz, Zhi-Xiong Jim Xiao
Activation of phosphatidylinositol 3 kinase (PI3K), Ras, and Her2 signaling plays a critical role in cancer development. Hotspot constitutive activating mutations in oncogenes, such as PIK3CA encoding the p110α catalytic subunit or RAS, as well as overexpression of Her2, are frequently found in human tumors and cancers. It has been well established that activation of these oncogenes profoundly promotes tumor metastasis, whereas decreased expression of ΔNp63α, the major protein isoform of the p53-related p63 expressed in epithelial cells, has been associated with cancer metastasis...
May 3, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28462395/calmodulin-and-pi3k-signaling-in-kras-cancers
#8
Ruth Nussinov, Guanqiao Wang, Chung-Jung Tsai, Hyunbum Jang, Shaoyong Lu, Avik Banerjee, Jian Zhang, Vadim Gaponenko
Calmodulin (CaM) uniquely promotes signaling of oncogenic K-Ras; but not N-Ras or H-Ras. How CaM interacts with K-Ras and how this stimulates cell proliferation are among the most challenging questions in KRAS-driven cancers. Earlier data pointed to formation of a ternary complex consisting of K-Ras, PI3Kα and CaM. Recent data point to phosphorylated CaM binding to the SH2 domains of the p85 subunit of PI3Kα and activating it. Modeling suggests that the high affinity interaction between the phosphorylated CaM tyrosine motif and PI3Kα, can promote full PI3Kα activation by oncogenic K-Ras...
March 2017: Trends in Cancer
https://www.readbyqxmd.com/read/28457754/investigation-of-the-structural-requirements-of-k-ras-g12d-selective-inhibitory-peptide-krpep-2d-using-alanine-scans-and-cysteine-bridging
#9
Ayumu Niida, Shigekazu Sasaki, Kazuko Yonemori, Tomoya Sameshima, Masahiro Yaguchi, Taiji Asami, Kotaro Sakamoto, Masahiro Kamaura
A structure-activity relationship study of a K-Ras(G12D) selective inhibitory cyclic peptide, KRpep-2d was performed. Alanine scanning of KRpep-2d focusing on the cyclic moiety showed that Leu(7), Ile(9), and Asp(12) are the key elements for K-Ras(G12D) selective inhibition of KRpep-2d. The cysteine bridging was also examined to identify the stable analog of KRpep-2d under reductive conditions. As a result, the KRpep-2d analog (12) including mono-methylene bridging showed potent K-Ras(G12D) selective inhibition in both the presence and the absence of dithiothreitol...
April 21, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28454210/statins-and-pancreatic-cancer
#10
Jun Gong, Esha Sachdev, Lori A Robbins, Emily Lin, Andrew E Hendifar, Monica M Mita
Pancreatic cancer remains among the most lethal cancers, despite ongoing advances in treatment for all stages of the disease. Disease prevention represents another opportunity to improve patient outcome, with metabolic syndrome and its components, such as diabetes, obesity and dyslipidemia, having been recognized as modifiable risk factors for pancreatic cancer. In addition, statins have been shown to potentially reduce pancreatic cancer risk and to improve survival in patients with a combination of metabolic syndrome and pancreatic cancer...
March 2017: Oncology Letters
https://www.readbyqxmd.com/read/28453172/phenotypic-classification-of-gastric-signet-ring-cell-carcinoma-and-its-relationship-with-k-ras-mutation
#11
Z F Xiong, J Shi, Z H Fu, H P Wan, L X Tu
We aimed to analyze gastric signet ring cell (SRC) carcinoma subtypes by investigating gastric and intestinal phenotypic marker expression, and explore the relationship between phenotype and K-ras mutation. Immunohistochemistry was performed on 163 SRC carcinoma patient specimens to detect gastric (MUC1, MUC5AC, and MUC6) and intestinal (MUC2 and CDX2) phenotypic markers, and tumors were classified into gastric (G), intestinal (I), and gastrointestinal (GI) phenotypes. DNA was extracted from the formalin-fixed, paraffin-embedded tumor samples, and K-ras mutations in codons 12, 13, and 61 were identified using polymerase chain reaction-based direct DNA sequencing...
April 28, 2017: Genetics and Molecular Research: GMR
https://www.readbyqxmd.com/read/28446465/deletion-of-lactate-dehydrogenase-a-in-myeloid-cells-triggers-antitumor-immunity
#12
Pankaj Seth, Eva Csizmadia, Andreas Hedblom, Marta Vuerich, Han Xie, Mailin Li, Maria Serena Longhi, Barbara Wegiel
Immunometabolism is emerging as a critical determinant of cancer pathophysiology. In this study, we explored the contributions of macrophage-expressed lactate dehydrogenase-A (LDH-A) to tumor formation in a K-Ras murine model of lung carcinoma. Myeloid-specific deletion of LDH-A promoted accumulation of macrophages with a CD86high and MCP-1high M1-like phenotype that suppressed tumor growth. This phenotypic effect was accompanied by reduced VEGF expression and angiogenesis; diminished numbers of PD-L1+ cancer cells; increased numbers of CD3+ T cells and activation status of CD8+ T cells...
April 26, 2017: Cancer Research
https://www.readbyqxmd.com/read/28435453/sirna-delivery-with-pegylated-graphene-oxide-nanosheets-for-combined-photothermal-and-genetherapy-for-pancreatic-cancer
#13
Feng Yin, Kuan Hu, Yangzi Chen, Mengying Yu, Dongyuan Wang, Qianqian Wang, Ken-Tye Yong, Fei Lu, Yongye Liang, Zigang Li
Since the successful exfoliation of graphene from graphite in 2004, graphene and graphene oxide (GO) have been considered the most promising two-dimensional (2D) nanomaterials with distinguished physical and chemical characteristics and have attracted great attention in many different fields. Graphene oxide is well-known for its distinct physiochemical properties and shows only minimal cytotoxicity compared to carbon nanotubes. Until now, only limited efforts have been invested in utilizing GO for gene therapy in pancreatic cancer treatments...
2017: Theranostics
https://www.readbyqxmd.com/read/28428697/geraniol-inhibits-endometrial-carcinoma-via-downregulating-oncogenes-and-upregulating-tumour-suppressor-genes
#14
Sakkaravarthy Shanmugapriya, Perumal Subramanian, Sivamani Kanimozhi
Endometrial carcinoma is the fourth most abundant cancer worldwide in women. Female Wistar rats were segregated into five groups: group I-control, group II-MNNG (N-methyl-N'-nitro-N-nitrosoguanidine-150 mg/kg) administered through intravaginal detention of cotton absorbent, group III-geraniol (GOH) only, group IV-GOH-pretreated (7 days before the start of MNNG administration); and group V-Co-administration of geraniol with MNNG. In this study, reverse transcriptase- PCR of K-ras, MAPK, PI3K, Wnt/β-catenin genes, TGF-β and expressions of PCNA, PTEN, progesterone receptor and E-cadherin by Western blotting were performed from endometrial cancer tissue and control tissues...
June 2017: Indian Journal of Clinical Biochemistry: IJCB
https://www.readbyqxmd.com/read/28426398/k-ras-and-n-ras-mutations-in-testicular-germ-cell-tumors
#15
Bekir Muhammet Hacioglu, Hilmi Kodaz, Bulent Erdogan, Ahmet Cinkaya, Ebru Tastekin, Ilhan Hacibekiroglu, Esma Turkmen, Osman Kostek, Ezgi Genc, Sernaz Uzunoglu, Irfan Cicin
Testicular cancer is a relatively rare tumor type, accounting for approximately 1% of all cancers in men. However, among men aged between 15 and 40 years, testicular cancer is the most commonly diagnosed malignancy. Testicular germ cell tumors (TGCTs) are classified as seminoma and non-seminoma. The RAS oncogene controls several cellular functions, including cell proliferation, apoptosis, migration, and differentiation. Thus, RAS signaling is important for normal germ cell development. Mutations of the Kirsten RAS (K-RAS) gene are present in over 20% of all cancers...
April 20, 2017: Bosnian Journal of Basic Medical Sciences
https://www.readbyqxmd.com/read/28423707/tropomyosin-related-kinase-b-mediated-signaling-contributes-to-the-induction-of-malignant-phenotype-of-gallbladder-cancer
#16
Makoto Kawamoto, Hideya Onishi, Keigo Ozono, Akio Yamasaki, Akira Imaizumi, Sachiko Kamakura, Kenji Nakano, Yoshinao Oda, Hideki Sumimoto, Masafumi Nakamura
This study aims to demonstrate the clinical and biological significance of Brain derived neurotrophic factor (BDNF)/Tropomyosin-related kinase B (TrkB) signaling in gallbladder cancer (GBC) through a series of in vitro and in vivo experiments. TrkB expression was detected in 63 (91.3%) out of 69 surgically resected primary GBC specimens by immunohistochemistry. TrkB expression in the invasive front correlated with T factor (p=0.0391) and clinical staging (p=0.0391). Overall survival was lower in patients with high TrkB expression in the invasive front than in those with low TrkB expression (p=0...
March 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/28415732/additional-k-ras-mutation-analysis-and-plectin-1-staining-improve-the-diagnostic-accuracy-of-pancreatic-solid-mass-in-eus-guided-fine-needle-aspiration
#17
Joo Kyung Park, Woo Hyun Paik, Byeong Jun Song, Ji Kon Ryu, Min A Kim, Jin Myung Park, Sang Hyub Lee, Yong-Tae Kim
BACKGROUND: One of the major genetic alterations in pancreatic ductal adenocarcinoma (PDAC) is the point mutation of K-ras gene. Plectin-1 was also recently identified as PDAC specific biomarker. The aim of this study was to investigate the improvement of diagnostic accuracy of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) by using additional K-ras mutation analysis and Plectin-1 staining in patients with pancreatic mass. METHODS: A total of 85 study patients with pancreatic mass underwent EUS-FNA and the final diagnoses were as follows; PDACs: 70 patients, pancreas neuroendocrine tumor: 4, metastasis to pancreas: 5, autoimmune pancreatitis: 3, chronic pancreatitis: 1, tuberculous lymphadenitis: 1, pseudocyst: 1...
March 11, 2017: Oncotarget
https://www.readbyqxmd.com/read/28415683/suppression-of-pkc-causes-oncogenic-stress-for-triggering-apoptosis-in-cancer-cells
#18
Suthakar Ganapathy, Bo Peng, Ling Shen, Tianqi Yu, Jean Lafontant, Ping Li, Rui Xiong, Alexandros Makriyannis, Changyan Chen
Gain of functional mutations in ras occurs in more than 30% of human malignancies and in particular 90% of pancreatic cancer. Mutant ras, via activating multiple effector pathways, not only promote cell growth or survival, but also apoptosis, depending upon cell types or circumstances. In order to further study the mechanisms of apoptosis induced by oncogenic ras, we employed the ras loop mutant genes and demonstrated that Akt functioned downstream of Ras in human pancreatic cancer or HPNE cells ectopically expressing mutated K-ras for the induction of apoptosis after the concurrent suppression of PKC α and β...
May 9, 2017: Oncotarget
https://www.readbyqxmd.com/read/28396365/a-novel-galectin-1-inhibitor-discovered-through-one-bead-two-compounds-library-potentiates-the-anti-tumor-effects-of-paclitaxel-in-vivo
#19
Tsung-Chieh Shih, Ruiwu Liu, Gabriel Fung, Gaurav Bhardwaj, Paramita M Ghosh, Kit S Lam
Through the one-bead two-compound (OB2C) ultra-high throughput screening method, we discovered a new small molecule compound LLS2 that can kill a variety of cancer cells. Pull-down assay and LC MS/MS indicated that galectin-1 is the target protein of LLS2. Galectin-1 is known to be involved in the regulation of proliferation, apoptosis, cell cycle, and angiogenesis. Binding of LLS2 to galectin-1 decreased membrane-associated H-Ras and K-Ras, and contributed to the suppression of pErk pathway. Importantly, combination of LLS2 with paclitaxel (a very important clinical chemotherapeutic agent) was found to exhibit synergistic activity against several human cancer cell lines (ovarian cancer, pancreatic cancer, and breast cancer cells) in vitro Furthermore, in vivo therapeutic study indicated that combination treatment with paclitaxel and LLS2 significantly inhibits the growth of ovarian cancer xenografts in athymic mice...
April 10, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28392908/shared-genetic-influences-between-dimensional-asd-and-adhd-symptoms-during-child-and-adolescent-development
#20
Evie Stergiakouli, George Davey Smith, Joanna Martin, David H Skuse, Wolfgang Viechtbauer, Susan M Ring, Angelica Ronald, David E Evans, Simon E Fisher, Anita Thapar, Beate St Pourcain
BACKGROUND: Shared genetic influences between attention-deficit/hyperactivity disorder (ADHD) symptoms and autism spectrum disorder (ASD) symptoms have been reported. Cross-trait genetic relationships are, however, subject to dynamic changes during development. We investigated the continuity of genetic overlap between ASD and ADHD symptoms in a general population sample during childhood and adolescence. We also studied uni- and cross-dimensional trait-disorder links with respect to genetic ADHD and ASD risk...
2017: Molecular Autism
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