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https://read.qxmd.com/read/30770874/loss-of-glutathione-redox-homeostasis-impairs-proteostasis-by-inhibiting-autophagy-dependent-protein-degradation
#1
David Guerrero-Gómez, José Antonio Mora-Lorca, Beatriz Sáenz-Narciso, Francisco José Naranjo-Galindo, Fernando Muñoz-Lobato, Cristina Parrado-Fernández, Julen Goikolea, Ángel Cedazo-Minguez, Christopher D Link, Christian Neri, María Dolores Sequedo, Rafael P Vázquez-Manrique, Elena Fernández-Suárez, Veit Goder, Roser Pané, Elisa Cabiscol, Peter Askjaer, Juan Cabello, Antonio Miranda-Vizuete
In the presence of aggregation-prone proteins, the cytosol and endoplasmic reticulum (ER) undergo a dramatic shift in their respective redox status, with the cytosol becoming more oxidized and the ER more reducing. However, whether and how changes in the cellular redox status may affect protein aggregation is unknown. Here, we show that C. elegans loss-of-function mutants for the glutathione reductase gsr-1 gene enhance the deleterious phenotypes of heterologous human, as well as endogenous worm aggregation-prone proteins...
February 15, 2019: Cell Death and Differentiation
https://read.qxmd.com/read/30758984/quantifying-uncertainty-and-robustness-in-a-biomathematical-model-based-patient-specific-response-metric-for-glioblastoma
#2
Andrea Hawkins-Daarud, Sandra K Johnston, Kristin R Swanson
PURPOSE: Glioblastomas, lethal primary brain tumors, are known for their heterogeneity and invasiveness. A growing body of literature has been developed demonstrating the clinical relevance of a biomathematical model, the proliferation-invasion model, of glioblastoma growth. Of interest here is the development of a treatment response metric, days gained (DG). This metric is based on individual tumor kinetics estimated through segmented volumes of hyperintense regions on T1-weighted gadolinium-enhanced and T2-weighted magnetic resonance images...
February 2019: JCO Clinical Cancer Informatics
https://read.qxmd.com/read/30758727/derivation-of-combined-species-sensitivity-distributions-for-acute-toxicity-of-pyrethroids-to-aquatic-animals
#3
Jeffrey M Giddings, Jeffrey Wirtz, David Campana, Michael Dobbs
The aquatic toxicity profiles of synthetic pyrethroid insecticides are remarkably similar, and results for a large number of species can be combined across compounds in Species Sensitivity Distributions (SSDs). Normalizing acute toxicity values (median lethal concentrations, LC50s) for each species and each pyrethroid to the LC50 of the same pyrethroid to the freshwater amphipod Hyalella azteca (the most sensitive species to all pyrethroids tested) enabled expression of LC50s as Hyalella equivalents that can be pooled across pyrethroids...
February 13, 2019: Ecotoxicology
https://read.qxmd.com/read/30755439/combined-aurora-kinase-a-aurka-and-wee1-inhibition-demonstrates-synergistic-antitumor-effect-in-squamous-cell-carcinoma-of-the-head-and-neck
#4
Jong Woo Lee, Janaki Parameswaran, Teresa Sandoval-Schaefer, Kyung Jin Eoh, Dong-Hua Yang, Fang Zhu, Ranee Mehra, Roshan Sharma, Stephen G Gaffney, Elizabeth B Perry, Jeffrey P Townsend, Ilya G Serebriiskii, Erica A Golemis, Natalia Issaeva, Wendell G Yarbrough, Ja Seok Koo, Barbara A Burtness
PURPOSE: Human papillomavirus (HPV)-negative head and neck squamous cell carcinomas (HNSCC) commonly bear disruptive mutations in TP53, resulting in treatment resistance. In these patients, direct targeting of p53 has not been successful, but synthetic lethal approaches have promise. Although Aurora A kinase (AURKA) is overexpressed and an oncogenic driver, its inhibition has only modest clinical effects in HPV-negative HNSCC. We explored a novel combination of AURKA and WEE1 inhibition to overcome intrinsic resistance to AURKA inhibition...
February 12, 2019: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://read.qxmd.com/read/30745338/synthetic-lethality-of-cytolytic-hsv-1-in-cancer-cells-with-atrx-and-pml-deficiency
#5
Mingqi Han, Christine E Napier, Sonja Frölich, Erdahl Teber, Ted Wong, Jane R Noble, Eugene H Y Choi, Roger D Everett, Anthony J Cesare, Roger R Reddel
Cancers that utilize the Alternative Lengthening of Telomeres (ALT) mechanism for telomere maintenance are often difficult to treat and have a poor prognosis. They are also commonly deficient for expression of ATRX protein, a repressor of ALT activity, and a component of PML nuclear bodies (PML NBs) which are required for intrinsic immunity to various viruses. Here we asked whether ATRX-deficiency creates a vulnerability in ALT cancer cells that could be exploited for therapeutic purposes. We showed in a range of cell types that a mutant herpes simplex virus type 1 (HSV-1) lacking ICP0, a protein that degrades PML NB components including ATRX, was ten- to one thousand-fold more effective in killing ATRX-deficient cells...
February 11, 2019: Journal of Cell Science
https://read.qxmd.com/read/30737343/mitochondrial-citrate-transporters-ctpa-and-yhma-are-required-for-extracellular-citric-acid-accumulation-and-contribute-to-cytosolic-acetyl-coa-generation-in-aspergillus-luchuensis-mut-kawachii
#6
Chihiro Kadooka, Kosuke Izumitsu, Masahira Onoue, Kayu Okutsu, Yumiko Yoshizaki, Kazunori Takamine, Masatoshi Goto, Hisanori Tamaki, Taiki Futagami
Aspergillus luchuensis mut . kawachii produces a large amount of citric acid during the process of fermenting shochu, a traditional Japanese distilled spirit. In this study, we characterized A. kawachii CtpA and YhmA, which are homologous to the yeast Saccharomyces cerevisiae mitochondrial citrate transporters Ctp1 and Yhm2, respectively. CtpA and YhmA were purified from A. kawachii and reconstituted into liposomes. The proteoliposomes exhibited only counter-exchange transport activity; CtpA transported citrate using counter substrates especially for cis -aconitate and malate, whereas YhmA transported citrate using a wider variety of counter substrates, including citrate, 2-oxoglutarate, malate, cis -aconitate, and succinate...
February 8, 2019: Applied and Environmental Microbiology
https://read.qxmd.com/read/30737214/drugging-rb1-deficiency-synthetic-lethality-with-aurora-kinases
#7
Frederick A Dick, Shawn Shun-Cheng Li
Two recent reports describe pharmacologic approaches to specifically treat RB1 -mutant cancers. The basis of this approach is a synthetic lethal relationship between RB1 mutations and inhibition of Aurora kinases A or B. See related article by Oser et al., p. 230 . See related article by Gong et al., p. 248 .
February 2019: Cancer Discovery
https://read.qxmd.com/read/30734910/toxicity-and-developmental-effect-of-cucurbitacin-e-from-citrullus-colocynthis-l-cucurbitales-cucurbitaceae-against-spodoptera-litura-fab-and-a-non-target-earthworm-eisenia-fetida-savigny
#8
Athirstam Ponsankar, Kitherian Sahayaraj, Sengottayan Senthil-Nathan, Prabhakaran Vasantha-Srinivasan, Sengodan Karthi, Annamalai Thanigaivel, Ganesan Petchidurai, Mariappan Madasamy, Wayne B Hunter
Pest management with natural botanical insecticides is a significant implementation for the sustainability of agroecosystem by reducing the unnecessary risk from the inputs of synthetic insecticides. In this research, we isolated the bioactive compound cucurbitacin E from Citrullus colocynthis (L.) Schrad, and their toxicological effects were screened against different larval instars of Spodoptera litura. The bioactive compound cucurbitacin E was chemically characterized through TLC, FT-IR, and NMR analyses...
February 8, 2019: Environmental Science and Pollution Research International
https://read.qxmd.com/read/30723117/ezh2-cooperates-with-gain-of-function-p53-mutants-to-promote-cancer-growth-and-metastasis
#9
Yu Zhao, Liya Ding, Dejie Wang, Zhenqing Ye, Yundong He, Linlin Ma, Runzhi Zhu, Yunqian Pan, Qiang Wu, Kun Pang, Xiaonan Hou, Saravut J Weroha, Conghui Han, Roger Coleman, Ilsa Coleman, R Jeffery Karnes, Jun Zhang, Peter S Nelson, Liguo Wang, Haojie Huang
In light of the increasing number of identified cancer-driven gain-of-function (GOF) mutants of p53, it is important to define a common mechanism to systematically target several mutants, rather than developing strategies tailored to inhibit each mutant individually. Here, using RNA immunoprecipitation-sequencing (RIP-seq), we identified the Polycomb-group histone methyltransferase EZH2 as a p53 mRNA-binding protein. EZH2 bound to an internal ribosome entry site (IRES) in the 5'UTR of p53 mRNA and enhanced p53 protein translation in a methyltransferase-independent manner...
February 5, 2019: EMBO Journal
https://read.qxmd.com/read/30718919/a-novel-proteotoxic-combination-therapy-for-egfr-and-her2-cancers
#10
Mengxiong Wang, Renan B Ferreira, Mary E Law, Bradley J Davis, Elham Yaaghubi, Amanda F Ghilardi, Abhisheak Sharma, Bonnie A Avery, Edgardo Rodriguez, Chi-Wu Chiang, Satya Narayan, Coy D Heldermon, Ronald K Castellano, Brian K Law
While HER2 and EGFR are overexpressed in breast cancers and multiple other types of tumors, the use of EGFR and/or HER2 inhibitors have failed to cure many cancer patients, largely because cancers acquire resistance to HER2/EGFR-specific drugs. Cancers that overexpress the HER-family proteins EGFR, HER2, and HER3 are uniquely sensitive to agents that disrupt HER2 and EGFR protein folding. We previously showed that disruption of disulfide bond formation by Disulfide Disrupting Agents (DDAs) kills HER2/EGFR overexpressing cells through multiple mechanisms...
February 4, 2019: Oncogene
https://read.qxmd.com/read/30718506/smarca4-loss-is-synthetic-lethal-with-cdk4-6-inhibition-in-non-small-cell-lung-cancer
#11
Yibo Xue, Brian Meehan, Zheng Fu, Xue Qing D Wang, Pierre Olivier Fiset, Ralf Rieker, Cameron Levins, Tim Kong, Xianbing Zhu, Geneviève Morin, Lashanda Skerritt, Esther Herpel, Sriram Venneti, Daniel Martinez, Alexander R Judkins, Sungmi Jung, Sophie Camilleri-Broet, Anne V Gonzalez, Marie-Christine Guiot, William W Lockwood, Jonathan D Spicer, Abbas Agaimy, William A Pastor, Josée Dostie, Janusz Rak, William D Foulkes, Sidong Huang
Tumor suppressor SMARCA4 (BRG1), a key SWI/SNF chromatin remodeling gene, is frequently inactivated in cancers and is not directly druggable. We recently uncovered that SMARCA4 loss in an ovarian cancer subtype causes cyclin D1 deficiency leading to susceptibility to CDK4/6 inhibition. Here, we show that this vulnerability is conserved in non-small cell lung cancer (NSCLC), where SMARCA4 loss also results in reduced cyclin D1 expression and selective sensitivity to CDK4/6 inhibitors. In addition, SMARCA2, another SWI/SNF subunit lost in a subset of NSCLCs, also regulates cyclin D1 and drug response when SMARCA4 is absent...
February 4, 2019: Nature Communications
https://read.qxmd.com/read/30718357/novel-third-generation-egfr-tyrosine-kinase-inhibitors-and-strategies-to-overcome-therapeutic-resistance-in-lung-cancer
#12
REVIEW
Ayesha Murtuza, Ajaz Bulbul, John Paul Shen, Parissa Keshavarzian, Brian D Woodward, Fernando J Lopez-Diaz, Scott M Lippman, Hatim Husain
EGFR-activating mutations are observed in approximately 15% to 20% of patients with non-small cell lung cancer. Tyrosine kinase inhibitors have provided an illustrative example of the successes in targeting oncogene addiction in cancer and the role of tumor-specific adaptations conferring therapeutic resistance. The compound osimertinib is a third-generation tyrosine kinase inhibitor, which was granted full FDA approval in March 2017 based on targeting EGFR T790M resistance. The compound has received additional FDA approval as first-line therapy with improvement in progression-free survival by suppressing the activating mutation and preventing the rise of the dominant resistance clone...
February 4, 2019: Cancer Research
https://read.qxmd.com/read/30709805/mapk-pathway-suppression-unmasks-latent-dna-repair-defects-and-confers-a-chemical-synthetic-vulnerability-in-braf-nras-and-nf1-mutant-melanomas
#13
Ophelia Maertens, Ryan Kuzmickas, Haley E Manchester, Chloe E Emerson, Alessandra G Gavin, Caroline J Guild, Terence C Wong, Thomas De Raedt, Christian Bowman-Colin, Elodie Hatchi, Levi A Garraway, Keith T Flaherty, Shailja Pathania, Stephen J Elledge, Karen Cichowski
While the majority of BRAF-mutant melanomas respond to BRAF/MEK inhibitors, these agents are not typically curative. Moreover, they are largely ineffective in NRAS- and NF1-mutant tumors. Here we report that genetic and chemical suppression of HDAC3 potently cooperates with MAPK pathway inhibitors in all three Ras pathway-driven tumors. Specifically, we show that entinostat dramatically enhances tumor regression when combined with BRAF/MEK inhibitors, both in models that are sensitive or relatively resistant to these agents...
February 1, 2019: Cancer Discovery
https://read.qxmd.com/read/30705406/akt-inhibition-impairs-pcna-ubiquitylation-and-triggers-synthetic-lethality-in-homologous-recombination-deficient-cells-submitted-to-replication-stress
#14
Florencia Villafañez, Iris Alejandra García, Sofia Carbajosa, María Florencia Pansa, Sabrina Mansilla, María Candelaria Llorens, Virginia Angiolini, Laura Guantay, Heinz Jacobs, Kevin P Madauss, Israel Gloger, Vanesa Gottifredi, Jose Luis Bocco, Gaston Soria
Translesion DNA synthesis (TLS) and homologous recombination (HR) cooperate during S-phase to safeguard replication forks integrity. Thus, the inhibition of TLS becomes a promising point of therapeutic intervention in HR-deficient cancers, where TLS impairment might trigger synthetic lethality (SL). The main limitation to test this hypothesis is the current lack of selective pharmacological inhibitors of TLS. Herein, we developed a miniaturized screening assay to identify inhibitors of PCNA ubiquitylation, a key post-translational modification required for efficient TLS activation...
January 31, 2019: Oncogene
https://read.qxmd.com/read/30704900/brca1-haploinsufficiency-is-masked-by-rnf168-mediated-chromatin-ubiquitylation
#15
Dali Zong, Salomé Adam, Yifan Wang, Hiroyuki Sasanuma, Elsa Callén, Matilde Murga, Amanda Day, Michael J Kruhlak, Nancy Wong, Meagan Munro, Arnab Ray Chaudhuri, Baktiar Karim, Bing Xia, Shunichi Takeda, Neil Johnson, Daniel Durocher, André Nussenzweig
BRCA1 functions at two distinct steps during homologous recombination (HR). Initially, it promotes DNA end resection, and subsequently it recruits the PALB2 and BRCA2 mediator complex, which stabilizes RAD51-DNA nucleoprotein filaments. Loss of 53BP1 rescues the HR defect in BRCA1-deficient cells by increasing resection, suggesting that BRCA1's downstream role in RAD51 loading is dispensable when 53BP1 is absent. Here we show that the E3 ubiquitin ligase RNF168, in addition to its canonical role in inhibiting end resection, acts in a redundant manner with BRCA1 to load PALB2 onto damaged DNA...
January 10, 2019: Molecular Cell
https://read.qxmd.com/read/30695077/the-cdk8-19-cyclin-c-transcription-regulator-functions-in-genome-replication-through-metazoan-sld7
#16
Kerstin Köhler, Luis Sanchez-Pulido, Verena Höfer, Anika Marko, Chris P Ponting, Ambrosius P Snijders, Regina Feederle, Aloys Schepers, Dominik Boos
Accurate genome duplication underlies genetic homeostasis. Metazoan Mdm2 binding protein (MTBP) forms a main regulatory platform for origin, firing together with Topoisomerase II binding protein 1 (TopBP1)-interacting replication stimulating protein/TopBP1-interacting checkpoint and replication regulator (Treslin/TICRR) and TopBP1. We report the first comprehensive analysis of MTBP and reveal conserved and metazoa-specific MTBP functions in replication. This suggests that metazoa have evolved specific molecular mechanisms to adapt replication principles conserved with yeast to the specific requirements of the more complex metazoan cells...
January 29, 2019: PLoS Biology
https://read.qxmd.com/read/30692507/spif-promotes-myoblast-differentiation-and-utrophin-expression-while-inhibiting-fibrosis-in-duchenne-muscular-dystrophy-via-the-h19-mir-675-let-7-and-mir-21-pathways
#17
Daria Morgoulis, Peter Berenstein, Simona Cazacu, Gila Kazimirsky, Amir Dori, Eytan R Barnea, Chaya Brodie
Duchenne muscular dystrophy (DMD) is a progressive, lethal, X-linked disease of skeletal and cardiac muscles caused by mutations in the dystrophin gene. Loss of dystrophin leads to muscle fiber damage and impairment of satellite cell asymmetric division, which are essential for muscle regeneration. These processes ultimately result in muscle wasting and the replacement of the degenerating muscles by fibrogenic cells, a process that leads to the generation of fibrotic tissues. Preimplantation factor (PIF) is an evolutionary conserved 15-amino acid peptide secreted by viable mammalian embryos...
January 28, 2019: Cell Death & Disease
https://read.qxmd.com/read/30692209/autophagy-modulates-lipid-metabolism-to-maintain-metabolic-flexibility-for-lkb1-deficient-kras-driven-lung-tumorigenesis
#18
Vrushank Bhatt, Khoosheh Khayati, Zhixian Sherrie Hu, Amy Lee, Wali Kamran, Xiaoyang Su, Jessie Yanxiang Guo
Loss of tumor suppressor liver kinase B1 (LKB1) promotes cancer cell proliferation but also leads to decreased metabolic plasticity in dealing with energy crises. Autophagy is a protective process involving self-cannibalization to maintain cellular energy homeostasis during nutrient deprivation. We developed a mouse model for Lkb1 -deficient lung cancer with conditional deletion of essential autophagy gene Atg7 to test whether autophagy compensates for LKB1 loss for tumor cells to survive energy crises. We found that autophagy ablation was synthetically lethal during Lkb1 -deficient lung tumorigenesis in both tumor initiation and tumor growth...
January 28, 2019: Genes & Development
https://read.qxmd.com/read/30691122/parp-1-2-inhibitor-olaparib-prevents-or-partially-reverts-emt-induced-by-tgf-%C3%AE-in-nmumg-cells
#19
Michelle Schacke, Janani Kumar, Nicholas Colwell, Kole Hermanson, Gustavo A Folle, Sergei Nechaev, Archana Dhasarathy, Laura Lafon-Hughes
Poly- adenosine diphosphate (ADP)-ribose (PAR) is a polymer synthesized as a posttranslational modification by some poly (ADP-ribose) polymerases (PARPs), namely PARP-1, PARP-2, tankyrase-1, and tankyrase-2 (TNKS-1/2). PARP-1 is nuclear and has also been detected in extracellular vesicles. PARP-2 and TNKS-1/2 are distributed in nuclei and cytoplasm. PARP or PAR alterations have been described in tumors, and in particular by influencing the Epithelial- Mesenchymal Transition (EMT), which influences cell migration and drug resistance in cancer cells...
January 26, 2019: International Journal of Molecular Sciences
https://read.qxmd.com/read/30686770/targeting-the-vulnerability-of-glutathione-metabolism-in-arid1a-deficient-cancers
#20
Hideaki Ogiwara, Kazuaki Takahashi, Mariko Sasaki, Takafumi Kuroda, Hiroshi Yoshida, Reiko Watanabe, Ami Maruyama, Hideki Makinoshima, Fumiko Chiwaki, Hiroki Sasaki, Tomoyasu Kato, Aikou Okamoto, Takashi Kohno
ARID1A encodes an SWI/SNF chromatin-remodeling factor and is frequently mutated in various cancers. This study demonstrates that ARID1A-deficient cancer cells are specifically vulnerable to inhibition of the antioxidant glutathione (GSH) and the glutamate-cysteine ligase synthetase catalytic subunit (GCLC), a rate-limiting enzyme for GSH synthesis. Inhibition of GCLC markedly decreased GSH in ARID1A-deficient cancer cells, leading to apoptotic cell death triggered by excessive amounts of reactive oxygen species...
January 16, 2019: Cancer Cell
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