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NAD+ AND cancer

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
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
Sanad Alonezi, Jonans Tusiimire, Jennifer Wallace, Mark J Dufton, John A Parkinson, Louise C Young, Carol J Clements, Jin Kyu Park, Jong Woon Jeon, Valerie A Ferro, David G Watson
In the present study, liquid chromatography-mass spectrometry (LC-MS) was employed to characterise the metabolic profiles of two human ovarian cancer cell lines A2780 (cisplatin-sensitive) and A2780CR (cisplatin-resistant) in response to their exposure to melittin, a cytotoxic peptide from bee venom. In addition, the metabolomics data were supported by application of Biolog microarray technology to examine the utilisation of carbon sources by the two cell lines. Data extraction with MZmine 2.14 and database searching were applied to provide metabolite lists...
October 13, 2016: Metabolites
Min Ji Bak, Van-Long Truong, Se-Yeon Ko, Xuan Ngan Giang Nguyen, Mira Jun, Soon-Gi Hong, Jong-Won Lee, Woo-Sik Jeong
BACKGROUND: The induction of cellular defensive genes such as phase II detoxifying and antioxidant enzymes is a highly effective strategy for protection against carcinogenesis as well as slowing cancer development. Transcription factor Nrf2 (nuclear factor E2-related factor 2) is responsible for activation of phase II enzymes induced by natural chemopreventive compounds. METHODS: Red ginseng oil (RGO) was extracted using a supercritical CO2 extraction system and chemical profile of RGO was investigated by GC/MS...
October 2016: Journal of Ginseng Research
Dan Y Gui, Lucas B Sullivan, Alba Luengo, Aaron M Hosios, Lauren N Bush, Nadege Gitego, Shawn M Davidson, Elizaveta Freinkman, Craig J Thomas, Matthew G Vander Heiden
Metformin use is associated with reduced cancer mortality, but how metformin impacts cancer outcomes is controversial. Although metformin can act on cells autonomously to inhibit tumor growth, the doses of metformin that inhibit proliferation in tissue culture are much higher than what has been described in vivo. Here, we show that the environment drastically alters sensitivity to metformin and other complex I inhibitors. We find that complex I supports proliferation by regenerating nicotinamide adenine dinucleotide (NAD)+, and metformin's anti-proliferative effect is due to loss of NAD+/NADH homeostasis and inhibition of aspartate biosynthesis...
October 12, 2016: Cell Metabolism
Wynand Paul Roos, Andrea Krumm
Histone/protein deacetylases play multiple roles in regulating gene expression and protein activation and stability. Their deregulation during cancer initiation and progression cause resistance to therapy. Here, we review the role of histone deacetylases (HDACs) and the NAD(+) dependent sirtuins (SIRTs) in the DNA damage response (DDR). These lysine deacetylases contribute to DNA repair by base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), non-homologous end joining (NHEJ), homologous recombination (HR) and interstrand crosslink (ICL) repair...
October 13, 2016: Nucleic Acids Research
Amy T Shah, Taylor M Cannon, James N Higginbotham, Robert J Coffey, Melissa C Skala
Clinical cancer treatment aims to target all cell subpopulations within a tumor. Autofluorescence microscopy of the metabolic cofactors NAD(P)H and FAD has shown sensitivity to anti-cancer treatment response. Alternatively, flow cytometry is attractive for high throughput analysis and flow sorting. This study measures cellular autofluorescence in three flow cytometry channels and applies cellular autofluorescence to sort a heterogeneous mixture of breast cancer cells into subpopulations enriched for each phenotype...
October 12, 2016: Journal of Biophotonics
Colin Thomas, Yingbiao Ji, Niraj Lodhi, Elena Kotova, Aaron Dan Pinnola, Konstantin Golovine, Peter Makhov, Kate Pechenkina, Vladimir Kolenko, Alexei V Tulin
The clinical potential of PARP-1 inhibitors has been recognized >10years ago, prompting intensive research on their pharmacological application in several branches of medicine, particularly in oncology. However, natural or acquired resistance of tumors to known PARP-1 inhibitors poses a serious problem for their clinical implementation. Present study aims to reignite clinical interest to PARP-1 inhibitors by introducing a new method of identifying highly potent inhibitors and presenting the largest known collection of structurally diverse inhibitors...
October 4, 2016: EBioMedicine
Asad Ali Shah, Akihiro Ito, Akiko Nakata, Minoru Yoshida
SIRT2 is a member of the human sirtuin family of proteins and possesses nicotinamide adenine dinucleotide (NAD)-dependent lysine deacetylase activity. SIRT2 has been involved in various cellular processes including gene transcription, genome constancy, and the cell cycle. In addition, SIRT2 is deeply implicated in diverse diseases including cancer. In this study, we identified a small molecule inhibitor of SIRT2 with a structure different from known SIRT2 inhibitors by screening from a chemical library. The hit compound showed a high selectivity toward SIRT2 as it only inhibited SIRT2, and not other sirtuins including SIRT1 and SIRT3 or zinc-dependent histone deacetylases (HDACs) including HDAC1 and HDAC6, in vitro...
2016: Biological & Pharmaceutical Bulletin
Yang Xiao, Mandy Kwong, Anneleen Daemen, Marcia Belvin, Xiaorong Liang, Georgia Hatzivassiliou, Thomas O'Brien
Nicotinamide adenine dinucleotide (NAD) is a cofactor involved in a wide range of cellular metabolic processes and is a key metabolite required for tumor growth. NAMPT, nicotinamide phosphoribosyltransferase, which converts nicotinamide (NAM) to nicotinamide mononucleotide (NMN), the immediate precursor of NAD, is an attractive therapeutic target as inhibition of NAMPT reduces cellular NAD levels and inhibits tumor growth in vivo. However, there is limited understanding of the metabolic response to NAD depletion across cancer cell lines and whether all cell lines respond in a uniform manner...
2016: PloS One
Jorgelindo da Veiga Moreira, Minoo Hamraz, Mohammad Abolhassani, Erwan Bigan, Sabine Pérès, Loïc Paulevé, Marcel Levy Nogueira, Jean-Marc Steyaert, Laurent Schwartz
To better understand the energetic status of proliferating cells, we have measured the intracellular pH (pHi) and concentrations of key metabolites, such as adenosine triphosphate (ATP), nicotinamide adenine dinucleotide (NAD), and nicotinamide adenine dinucleotide phosphate (NADP) in normal and cancer cells, extracted from fresh human colon tissues. Cells were sorted by elutriation and segregated in different phases of the cell cycle (G0/G1/S/G2/M) in order to study their redox (NAD, NADP) and bioenergetic (ATP, pHi) status...
October 3, 2016: Metabolites
Jie Zhuang, William M Kamp, Jie Li, Chengyu Liu, Ju-Gyeong Kang, Ping-Yuan Wang, Paul M Hwang
Although exercise is linked with improved health, the specific molecular mechanisms underlying its various benefits require further clarification. Here, we report that exercise increases the nuclear localization and activity of p53 by acutely down regulating coiled-coil-helix-coiled-coil-helix domain 4 (CHCHD4), a carrier protein that mediates p53 import into the mitochondria. This response to exercise is lost in transgenic mice with constitutive expression of CHCHD4. Mechanistically, exercise-induced nuclear transcription factor FOXO3 binds to the CHCHD4 promoter and represses its expression, preventing the translocation of p53 to the mitochondria and thereby increasing p53 nuclear localization...
September 29, 2016: Journal of Biological Chemistry
Katarzyna Lubelska, Katarzyna Wiktorska, Lidia Mielczarek, Małgorzata Milczarek, Ilona Zbroińska-Bregisz, Zdzisław Chilmonczyk
Sulforaphane (SFN), a naturally occurring chemopreventive and anticancer agent, is a nuclear factor, erythroid 2-like 2 (NFE2L2/Nrf2) inducer. Nrf2 plays a critical role in coordinating the cell defense system by initiating the transcription of cytoprotective genes, including detoxification enzymes such as NAD(P)H quinone dehydrogenase 1 (NQO1) and transport proteins such as ATP-binding cassette, subfamily C (CFTR/MRP). Recently, the essential role of Nrf2 in tumor development and progression and in the development of multidrug resistance in cancer cells has been highlighted...
September 16, 2016: Nutrition and Cancer
Lucie Brisson, Piotr Bański, Martina Sboarina, Coralie Dethier, Pierre Danhier, Marie-Joséphine Fontenille, Vincent F Van Hée, Thibaut Vazeille, Morgane Tardy, Jorge Falces, Caroline Bouzin, Paolo E Porporato, Raphaël Frédérick, Carine Michiels, Tamara Copetti, Pierre Sonveaux
Metabolic adaptability is essential for tumor progression and includes cooperation between cancer cells with different metabolic phenotypes. Optimal glucose supply to glycolytic cancer cells occurs when oxidative cancer cells use lactate preferentially to glucose. However, using lactate instead of glucose mimics glucose deprivation, and glucose starvation induces autophagy. We report that lactate sustains autophagy in cancer. In cancer cells preferentially to normal cells, lactate dehydrogenase B (LDHB), catalyzing the conversion of lactate and NAD(+) to pyruvate, NADH and H(+), controls lysosomal acidification, vesicle maturation, and intracellular proteolysis...
September 12, 2016: Cancer Cell
Hui-Ying Liu, Qing-Ran Li, Xue-Fang Cheng, Guang-Ji Wang, Hai-Ping Hao
Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the first rate-limiting step in converting nicotinamide to NAD(+), essential for a number of enzymes and regulatory proteins involved in a variety of cellular processes, including deacetylation enzyme SIRT1 which modulates several tumor suppressors such as p53 and FOXO. Herein we report that NQO1 substrates Tanshione IIA (TSA) and β-lapachone (β-lap) induced a rapid depletion of NAD(+) pool but adaptively a significant upregulation of NAMPT. NAMPT inhibition by FK866 at a nontoxic dose significantly enhanced NQO1-targeting agent-induced apoptotic cell death...
August 2016: Chinese Journal of Natural Medicines
Marcin Buler, Ulf Andersson, Jukka Hakkola
Sirtuins (SIRT1-7) are a family of nicotine adenine dinucleotide (NAD(+))-dependent enzymes that catalyze post-translational modifications of proteins. Together, they regulate crucial cellular functions and are traditionally associated with aging and longevity. Dysregulation of sirtuins plays an important role in major diseases, including cancer and metabolic, cardiac, and neurodegerative diseases. They are extensively regulated in response to a wide range of stimuli, including nutritional and metabolic challenges, inflammatory signals or hypoxic and oxidative stress...
September 2, 2016: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Philip M Tedeschi, Nitu Bansal, John E Kerrigan, Emine E Abali, Kathleen W Scotto, Joseph R Bertino
NAD(+) kinase (NADK) catalyzes the phosphorylation of nicotinamide adenine dinucleotide (NAD(+)) to nicotinamide adenine dinucleotide phosphate (NADP(+)) using ATP as the phosphate donor. NADP(+) is then reduced to NADPH by dehydrogenases, in particular glucose-6-phosphate dehydrogenase and the malic enzymes. NADPH functions as an important cofactor in a variety of metabolic and biosynthetic pathways. The demand for NADPH is particularly high in proliferating cancer cells, where it acts as a cofactor for the synthesis of nucleotides, proteins, and fatty acids...
August 31, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Masashi Tomida, Kuniyasu Okudaira, Takeshi Kamomae, Hiroshi Oguchi, Yoshikazu Miyake, Kazuo Yoneda, Yoshiyuki Itoh
The application of neoadjuvant androgen deprivation (NAD) in prostate cancer leads to a reduction in prostate volume, and the trends in volume reduction differ according to the treatment duration of NAD. A reduction in volume during external beam radiation therapy may lead to the exposure of normal tissues to an unexpected dose. In fact, prostate volume reductions have primarily been reported in European and American institutions. Although the prostate volume of Japanese patients is known to be small, the trends in prostate volume change during radiation therapy remain unclear...
August 2016: Nagoya Journal of Medical Science
Huiying Liu, Rong Xing, Xuefang Cheng, Qingran Li, Fang Liu, Hui Ye, Min Zhao, Hong Wang, Guangji Wang, Haiping Hao
Tryptophan metabolism is essential in diverse kinds of tumors via regulating tumor immunology. However, the direct role of tryptophan metabolism and its signaling pathway in cancer cells remain largely elusive. Here, we establish a mechanistic link from L-type amino acid transporter 1 (LAT1) mediated transport of tryptophan and the subsequent de-novo NAD+ synthesis to SIRT1-FOXO1 regulated apoptotic signaling in A549 cells in response to NQO1 activation. In response to NQO1 activation, SIRT1 is repressed leading to the increased cellular accumulation of acetylated FOXO1 that transcriptionally activates apoptotic signaling...
August 23, 2016: Oncotarget
Judith E Unterlass, Arnaud Baslé, Timothy J Blackburn, Julie Tucker, Céline Cano, Martin E M Noble, Nicola J Curtin
3-Phosphoglycerate dehydrogenase (PHGDH) has recently been identified as an attractive target in cancer therapy as it links upregulated glycolytic flux to increased biomass production in cancer cells. PHGDH catalyses the first step in the serine synthesis pathway and thus diverts glycolytic flux into serine synthesis. We have used siRNA-mediated suppression of PHGDH expression to show that PHGDH is a potential therapeutic target in PHGDH-amplified breast cancer. Knockdown caused reduced proliferation in the PHGDH-amplified cell line MDA-MB-468, whereas breast cancer cells with low PHGDH expression or with elevated PHGDH expression in the absence of genomic amplification were not affected...
August 22, 2016: Oncotarget
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