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NAD+ AND cancer

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https://www.readbyqxmd.com/read/27930300/an-nad-dependent-transcriptional-program-governs-self-renewal-and-radiation-resistance-in-glioblastoma
#1
Amit D Gujar, Son Le, Diane D Mao, David Y A Dadey, Alice Turski, Yo Sasaki, Diane Aum, Jingqin Luo, Sonika Dahiya, Liya Yuan, Keith M Rich, Jeffrey Milbrandt, Dennis E Hallahan, Hiroko Yano, David D Tran, Albert H Kim
Accumulating evidence suggests cancer cells exhibit a dependency on metabolic pathways regulated by nicotinamide adenine dinucleotide (NAD(+)). Nevertheless, how the regulation of this metabolic cofactor interfaces with signal transduction networks remains poorly understood in glioblastoma. Here, we report nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting step in NAD(+) synthesis, is highly expressed in glioblastoma tumors and patient-derived glioblastoma stem-like cells (GSCs). High NAMPT expression in tumors correlates with decreased patient survival...
December 7, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27929731/autophagic-homeostasis-is-required-for-the-pluripotency-of-cancer-stem-cells
#2
Tanveer Sharif, Emma Martell, Cathleen Dai, Barry E Kennedy, Patrick Murphy, Derek Clements, Youra Kim, Patrick W K Lee, Shashi Gujar
Pluripotency is an important feature of cancer stem cells (CSCs) that contributes to self-renewal and chemoresistance. The maintenance of pluripotency of CSCs under various pathophysiological conditions requires a complex interaction between various cellular pathways including those involved in homeostasis and energy metabolism. However, the exact mechanisms that maintain the CSC pluripotency remain poorly understood. In this report, using both human and murine models of CSCs, we demonstrate that basal levels of autophagy are required to maintain the pluripotency of CSCs, and that this process is differentially regulated by the rate limiting enzyme in the NAD(+) synthesis pathway NAMPT (nicotinamide phosphoribosyltransferase) and the transcription factor POU5F1/OCT4 (POU class 5 homeobox 1)...
December 8, 2016: Autophagy
https://www.readbyqxmd.com/read/27911769/reductive-carboxylation-is-a-major-metabolic-pathway-in-the-retinal-pigment-epithelium
#3
Jianhai Du, Aya Yanagida, Kaitlen Knight, Abbi L Engel, Anh Huan Vo, Connor Jankowski, Martin Sadilek, Van Thi Bao Tran, Megan A Manson, Aravind Ramakrishnan, James B Hurley, Jennifer R Chao
The retinal pigment epithelium (RPE) is a monolayer of pigmented cells that requires an active metabolism to maintain outer retinal homeostasis and compensate for oxidative stress. Using (13)C metabolic flux analysis in human RPE cells, we found that RPE has an exceptionally high capacity for reductive carboxylation, a metabolic pathway that has recently garnered significant interest because of its role in cancer cell survival. The capacity for reductive carboxylation in RPE exceeds that of all other cells tested, including retina, neural tissue, glial cells, and a cancer cell line...
December 1, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27899380/crystal-structure-of-the-emerging-cancer-target-mthfd2-in-complex-with-a-substrate-based-inhibitor
#4
Robert Gustafsson, Ann-Sofie Jemth, Nina Gustafsson Sheppard, Katarina Färnegårdh, Olga Loseva, Elisée Wiita, Nadilly Bonagas, Leif Dahllund, Sabin Llona-Minguez, Maria Häggblad, Martin Henriksson, Yasmin Andersson, Evert Homan, Thomas Helleday, Pål Stenmark
To sustain their proliferation, cancer cells become dependent on one-carbon metabolism to support purine and thymidylate synthesis. Indeed, one of the most highly upregulated enzymes during neoplastic transformation is MTHFD2, a mitochondrial methylenetetrahydrofolate dehydrogenase and cyclohydrolase involved in one-carbon metabolism. Since MTHFD2 is expressed normally only during embryonic development, it offers a disease-selective therapeutic target for eradicating cancer cells while sparing healthy cells...
November 29, 2016: Cancer Research
https://www.readbyqxmd.com/read/27897082/ameliorative-effect-of-an-oxovanadium-iv-complex-against-oxidative-stress-and-nephrotoxicity-induced-by-cisplatin
#5
Abhishek Basu, Arin Bhattacharjee, Subhadip Hajra, Amalesh Samanta, Sudin Bhattacharya
OBJECTIVE: The present study was designed to investigate the chemoprotective efficacy of an L-cysteine-based oxovanadium (IV) complex, namely, oxovanadium (IV)-L-cysteine methyl ester complex (VC-IV) against cisplatin (CDDP)-induced renal injury in Swiss albino mice. METHODS: CDDP was administered intraperitoneally (5 mg/kg body weight) and VC-IV was administered orally (1 mg/kg body weight) in concomitant and 7 days pre-treatment schedule. RESULTS: CDDP-treated mice showed marked kidney damage and renal failure...
November 29, 2016: Redox Report: Communications in Free Radical Research
https://www.readbyqxmd.com/read/27890529/mass-spectrometry-analysis-shows-the-biosynthetic-pathways-supported-by-pyruvate-carboxylase-in-highly-invasive-breast-cancer-cells
#6
Phatchariya Phannasil, Israr-Ul H Ansari, Mahmoud El Azzouny, Melissa J Longacre, Khanti Rattanapornsompong, Charles F Burant, Sarawut Jitrapakdee, Michael J MacDonald
We recently showed that the anaplerotic enzyme pyruvate carboxylase (PC) is up-regulated in human breast cancer tissue and its expression is correlated with the late stages of breast cancer and tumor size [Phannasil et al., PloS One 10, e0129848, 2015]. In the current study we showed that PC enzyme activity is much higher in the highly invasive breast cancer cell line MDA-MB-231 than in less invasive breast cancer cell lines. We generated multiple stable PC knockdown cell lines from the MDA-MB-231 cell line and used mass spectrometry with (13)C6-glucose and (13)C5-glutamine to discern the pathways that use PC in support of cell growth...
November 23, 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27889632/synthesis-biological-evaluation-and-in-silico-molecular-modeling-of-pyrrolyl-benzohydrazide-derivatives-as-enoyl-acp-reductase-inhibitors
#7
Shrinivas D Joshi, Sheshagiri R Dixit, Venkatarao H Kulkarni, Christian Lherbet, Mallikarjuna N Nadagouda, Tejraj M Aminabhavi
In efforts to develop lead anti-TB compounds, a novel series of 19 pyrrolyl benzohydrazides were synthesized and screened to target enoyl-ACP reductase enzyme, which is one of the important enzymes involved in type II fatty acid biosynthetic pathway of M. tuberculosis. Pharmacophores were constructed using GALAHAD to generate alignment of data sets and calculated by Pareto ranking. The pharmacophore features were then filtered by Surflex-dock study using enoyl ACP reductase from M. tuberculosis. Compounds 5b and 5d showed H-bonding interactions with Tyr158, Thr196 and co-factor NAD(+) that fitted well within the binding pocket of InhA...
November 17, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27875273/sirt2-regulates-nuclear-envelope-reassembly-via-ankle2-deacetylation
#8
Tanja Kaufmann, Eva Kukolj, Andreas Brachner, Etienne Beltzung, Melania Bruno, Sebastian Kostrhon, Susanne Opravil, Otto Hudecz, Karl Mechtler, Graham Warren, Dea Slade
Sirtuin 2 (SIRT2) is an NAD-dependent deacetylase known to regulate microtubule dynamics and cell cycle progression. SIRT2 has also been implicated in the pathology of cancer, neurodegenerative diseases and progeria. Here we show that SIRT2 depletion or overexpression causes nuclear envelope reassembly defects. We link this phenotype to the recently identified regulator of nuclear envelope reassembly ANKLE2. ANKLE2 acetylation at K302 and phosphorylation at S662 are dynamically regulated throughout the cell cycle by SIRT2 and are essential for normal nuclear envelope reassembly...
November 14, 2016: Journal of Cell Science
https://www.readbyqxmd.com/read/27860235/a-functional-pseudogene-nmral2p-is-regulated-by-nrf2-and-serves-as-a-co-activator-of-nqo1-in-sulforaphane-treated-colon-cancer-cells
#9
Gavin S Johnson, Jia Li, Laura M Beaver, W Mohaiza Dashwood, Deqiang Sun, Praveen Rajendran, David E Williams, Emily Ho, Roderick H Dashwood
SCOPE: The anticancer agent sulforaphane (SFN) acts via multiple mechanisms to modulate gene expression, including the induction of nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-dependent signaling and the inhibition of histone deacetylase activity. Transcriptomics studies were performed in SFN-treated human colon cancer cells and in non-transformed colonic epithelial cells in order to pursue new mechanistic leads. METHODS AND RESULTS: RNA-sequencing corroborated the expected changes in cancer-related pathways after SFN treatment...
November 18, 2016: Molecular Nutrition & Food Research
https://www.readbyqxmd.com/read/27858336/sirtuin-5-a-review-of-structure-known-inhibitors-and-clues-for-developing-new-inhibitors
#10
REVIEW
Lingling Yang, Xiaobo Ma, Yanying He, Chen Yuan, Quanlong Chen, Guobo Li, Xianggui Chen
Sirtuins (SIRTs) are nicotinamide adenine dinucleotide (NAD(+))-dependent protein deacetylases, which regulate important biological processes ranging from apoptosis, age-associated pathophysiologies, adipocyte and muscle differentiation, and energy expenditure to gluconeogenesis. Very recently, sirtuin 5 (SIRT5) has received considerable attention due to that it was found to have weak deacetylase activity but strong desuccinylase, demalonylase and deglutarylase activities, and it was also found to be associated with several human diseases such as cancer, Alzheimer's disease, and Parkinson's disease...
November 17, 2016: Science China. Life Sciences
https://www.readbyqxmd.com/read/27836583/sirt6-novel-mechanisms-and-links-to-aging-and-disease
#11
REVIEW
Luisa Tasselli, Wei Zheng, Katrin F Chua
SIRT6, a member of the Sirtuin family of NAD(+)-dependent enzymes, has established roles in chromatin signaling and genome maintenance. Through these functions, SIRT6 protects against aging-associated pathologies including metabolic disease and cancer, and can promote longevity in mice. Research from the past few years revealed that SIRT6 is a complex enzyme with multiple substrates and catalytic activities, and uncovered novel SIRT6 functions in the maintenance of organismal health span. Here, we review these new discoveries and models of SIRT6 biology in four areas: heterochromatin stabilization and silencing; stem cell biology; cancer initiation and progression; and regulation of metabolic homeostasis...
November 8, 2016: Trends in Endocrinology and Metabolism: TEM
https://www.readbyqxmd.com/read/27829520/affinity-based-small-fluorescent-probe-for-nad-p-h-quinone-oxidoreductase-1-nqo1-design-synthesis-and-pharmacological-evaluation
#12
Jinlei Bian, Xiang Li, Lili Xu, Nan Wang, Xue Qian, Qidong You, Xiaojin Zhang
NQO1 is a dimeric flavoprotein which intimately associated with cancer and overexpressed in the cytosol of numerous human tumor cells. Given that the cellular environment is quite dynamic and versatile, further investigation of the function of NQO1 depends on tools for specific detection of it. Currently, several activity-based assays have been developed to detect NQO1-expressing cancerous tissues. Herein, we report the development of a functional affinity-based small-molecule probe which is composed of a potent small-molecule NQO1 inhibitor 3d as the recognition group, a linker and the fluorophores group FITC...
November 1, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27829173/multiple-pathways-of-sirt6-at-the-crossroads-in-the-control-of-longevity-cancer-and-cardiovascular-diseases
#13
REVIEW
Milena Vitiello, Alberto Zullo, Luigi Servillo, Francesco Paolo Mancini, Adriana Borriello, Alfonso Giovane, Fulvio Della Ragione, Nunzia D'Onofrio, Maria Luisa Balestrieri
Sirtuin 6 (SIRT6) is a member of the sirtuin family NAD(+)-dependent deacetylases with multiple roles in controlling organism homeostasis, lifespan, and diseases. Due to its complex and opposite functional roles, this sirtuin is considered a two-edged sword in health and disease. Indeed, SIRT6 improves longevity, similarly to the founding yeast member, silent information regulator-2 (Sir2), and modulates genome stability, telomere integrity, transcription, and DNA repair. Its deficiency is associated with chronic inflammation, diabetes, cardiac hypertrophy, obesity, liver dysfunction, muscle/adipocyte disorders, and cancer...
November 6, 2016: Ageing Research Reviews
https://www.readbyqxmd.com/read/27817743/new-insights-into-the-roles-of-nad-poly-adp-ribose-metabolism-and-poly-adp-ribose-glycohydrolase
#14
Seiichi Tanuma, Akira Sato, Takahiro Oyama, Atsushi Yoshimori, Hideaki Abe, Fumiaki Uchiumi
Accumulating evidence has suggested the fundamental functions of NAD+-poly(ADP-ribose) metabolism in cellular and physiological processes, including energy homeostasis, signal transduction, DNA transaction, genomic stability and cell death or survival. The NAD+ biosynthesis and poly(ADP-ribose) [(ADP-R)n] turnover are tightly controlled by several key enzymes, such as nicotinamide phosphoribosyltransferase (NmPRT), nicotinamide mononucleotide adenylyltransferases (NMNATs), poly(ADP-ribose) polymerase (PARP), poly(ADP-ribose) glycohydrolase (PARG) and ADP-ribose pyrophosphorylase (ADPRPPL)...
2016: Current Protein & Peptide Science
https://www.readbyqxmd.com/read/27816507/nad-salvage-pathway-in-cancer-metabolism-and-therapy
#15
REVIEW
Barry E Kennedy, Tanveer Sharif, Emma Martell, Cathleen Dai, Youra Kim, Patrick W K Lee, Shashi A Gujar
Nicotinamide adenine dinucleotide (NAD(+)) is an essential coenzyme for various physiological processes including energy metabolism, DNA repair, cell growth, and cell death. Many of these pathways are typically dysregulated in cancer cells, making NAD(+) an intriguing target for cancer therapeutics. NAD(+) is mainly synthesized by the NAD(+) salvage pathway in cancer cells, and not surprisingly, the pharmacological targeting of the NAD(+) salvage pathway causes cancer cell cytotoxicity in vitro and in vivo...
November 2, 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/27806574/ado-keto-reductase-regulation-by-the-nrf2-system-implications-for-stress-response-chemotherapy-drug-resistance-and-carcinogenesis
#16
Trevor M Penning
Human Aldo-Keto Reductases are NAD(P)H dependent oxidoreductases that convert aldehydes and ketones to primary and secondary alcohols for subsequent conjugation reactions and can be referred to as "phase 1" enzymes. Among all the human genes regulated by the Keap1/Nrf2 pathway they are consistently the most overexpressed in response to Nrf2 activators. While these enzymes play clear cytoprotective roles and deal effectively with carbonyl stress, their up-regulation by the Keap1/Nrf2 pathway also has a potential dark-side, which can lead to chemotherapeutic drug resistance, and the metabolic activation of lung carcinogens (e...
November 3, 2016: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/27793057/hypermethylation-of-the-hic1-promoter-and-aberrant-expression-of-hic1-sirt1-contribute-to-the-development-of-thyroid-papillary-carcinoma
#17
Wenyi Wu, Liting Zhang, Jianqing Lin, Hanwei Huang, Bai Shi, Xingong Lin, Zhongxin Huang, Chaoyang Wang, Jianlong Qiu, Xiaolong Wei
Hypermethylation leading to the loss of hypermethylated in cancer-1 (HIC1) gene expression occurs in many different types of human cancer. HIC1 is a transcriptional repressor that directly binds to the promoter region of NAD-dependent deacetylase sirtuin-1 (SIRT1). SIRT1 functions in cell growth, is anti-apoptotic, protect neurons, functions in senescence, and regulates energy restriction. Epigenetic modification and dysregulation affecting the HIC1/SIRT1 axis is potentially important for the development of malignancies...
October 26, 2016: Oncotarget
https://www.readbyqxmd.com/read/27791271/sirt3-and-p53-deacetylation-in-aging-and-cancer
#18
REVIEW
Jijun Chen, Aiqin Wang, Qingqi Chen
The mammalian Sirtuins are a family of highly conserved nicotinamide adenine dinucleotide (NAD +)-dependent histone deacetylase. The mammalian Sirtuins family has identified seven different types of sirtuin. Sirtuins 3(SirT3) is localized to mitochondria, and is a multiple functional protein deacylase through deacetylating a variety of substrates. Cellular senescence represents a permanent withdraw from cell cycle in response to diverse stress; it is controlled by the p53 and retinoblastoma protein (RB) tumor suppressors, and constitutes a potent anticancer mechanisms...
October 28, 2016: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/27764779/mesenchymal-stem-cells-overexpressing-sirt1-inhibit-prostate-cancer-growth-by-recruiting-natural-killer-cells-and-macrophages
#19
Yang Yu, Qingyun Zhang, Qinggui Meng, Chen Zong, Lei Liang, Xue Yang, Rui Lin, Yan Liu, Yang Zhou, Hongxiang Zhang, Xiaojuan Hou, Zhipeng Han, Jiwen Cheng
Prostate cancer (PCa) has become the second leading cause of male cancer-related mortality in the United States. Mesenchymal stem cells (MSCs) are able to migrate to tumor tissues, and are thus considered to be novel antitumor carriers. However, due to their immunosuppressive nature, the application of MSCs in PCa therapy remains limited. In this study, we investigated the effect of MSCs overexpressing an NAD-dependent deacetylase sirtuin 1 (MSCs-Sirt1) on prostate tumor growth, and we analyzed the underlying mechanisms...
October 18, 2016: Oncotarget
https://www.readbyqxmd.com/read/27759097/crystal-structure-of-human-aldehyde-dehydrogenase-1a3-complexed-with-nad-and-retinoic-acid
#20
Andrea Moretti, Jianfeng Li, Stefano Donini, Robert W Sobol, Menico Rizzi, Silvia Garavaglia
The aldehyde dehydrogenase family 1 member A3 (ALDH1A3) catalyzes the oxidation of retinal to the pleiotropic factor retinoic acid using NAD(+). The level of ALDHs enzymatic activity has been used as a cancer stem cell marker and seems to correlate with tumour aggressiveness. Elevated ALDH1A3 expression in mesenchymal glioma stem cells highlights the potential of this isozyme as a prognosis marker and drug target. Here we report the first crystal structure of human ALDH1A3 complexed with NAD(+) and the product all-trans retinoic acid (REA)...
October 19, 2016: Scientific Reports
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