The Combination of Arginine Deprivation and 5-Fluorouracil Improves Therapeutic Efficacy in Argininosuccinate Synthetase Negative Hepatocellular Carcinoma.

Abstract:

:Argininosuccinate synthetase (ASS), a key enzyme to synthesize arginine is down regulated in many tumors including hepatocellular carcinoma (HCC). Similar to previous reports, we have found the decrease in ASS expression in poorly differentiated HCC. These ASS(-) tumors are auxotrophic for arginine. Pegylated arginine deiminase (ADI-PEG20), which degrades arginine, has shown activity in these tumors, but the antitumor effect is not robust and hence combination treatment is needed. Herein, we have elucidated the effectiveness of ADI-PEG20 combined with 5-Fluorouracil (5-FU) in ASS(-)HCC by targeting urea cycle and pyrimidine metabolism using four HCC cell lines as model. SNU398 and SNU387 express very low levels of ASS or ASS(-) while Huh-1, and HepG2 express high ASS similar to normal cells. Our results showed that the augmented cytotoxic effect of combination treatment only occurs in SNU398 and SNU387, and not in HepG2 and Huh-1 (ASS(+)) cells, and is partly due to reduced anti-apoptotic proteins X-linked inhibitor of apoptosis protein (XIAP), myeloid leukemia cell differentiation protein (Mcl-1) and B-cell lymphoma-2 (Bcl-2). Importantly, lack of ASS also influences essential enzymes in pyrimidine synthesis (carbamoyl-phosphate synthetase2, aspartate transcarbamylase and dihydrooratase (CAD) and thymidylate synthase (TS)) and malate dehydrogenase-1 (MDH-1) in TCA cycle. ADI-PEG20 treatment decreased these enzymes and made them more vulnerable to 5-FU. Transfection of ASS restored these enzymes and abolished the sensitivity to ADI-PEG20 and combination treatment. Overall, our data suggest that ASS influences multiple enzymes involved in 5-FU sensitivity. Combining ADI-PEG20 and 5-FU may be effective to treat ASS(-)hepatoma and warrants further clinical investigation.

journal_name

Int J Mol Sci

authors

Thongkum A,Wu C,Li YY,Wangpaichitr M,Navasumrit P,Parnlob V,Sricharunrat T,Bhudhisawasdi V,Ruchirawat M,Savaraj N

doi

10.3390/ijms18061175

subject

Has Abstract

pub_date

2017-06-01 00:00:00

issue

6

issn

1422-0067

pii

ijms18061175

journal_volume

18

pub_type

杂志文章
  • Ectopic expression of CsCTR1, a cucumber CTR-like gene, attenuates constitutive ethylene signaling in an Arabidopsis ctr1-1 mutant and expression pattern analysis of CsCTR1 in cucumber (Cucumis sativus).

    abstract::The gaseous plant hormone ethylene regulates many aspects of plant growth, development and responses to the environment. Constitutive triple response 1 (CTR1) is a central regulator involved in the ethylene signal transduction pathway. To obtain a better understanding of this particular pathway in cucumber, the cDNA-e...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章

    doi:10.3390/ijms150916331

    authors: Bie B,Sun J,Pan J,He H,Cai R

    更新日期:2014-09-15 00:00:00

  • Therapeutic Targeting of Collective Invasion in Ovarian Cancer.

    abstract::Ovarian cancer is the seventh most commonly diagnosed cancer amongst women and has the highest mortality rate of all gynaecological malignancies. It is a heterogeneous disease attributed to one of three cell types found within the reproductive milieu: epithelial, stromal, and germ cell. Each histotype differs in etiol...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章,评审

    doi:10.3390/ijms20061466

    authors: Moffitt L,Karimnia N,Stephens A,Bilandzic M

    更新日期:2019-03-22 00:00:00

  • Pharmacological Chaperones: A Therapeutic Approach for Diseases Caused by Destabilizing Missense Mutations.

    abstract::The term "pharmacological chaperone" was introduced 20 years ago. Since then the approach with this type of drug has been proposed for several diseases, lysosomal storage disorders representing the most popular targets. The hallmark of a pharmacological chaperone is its ability to bind a protein specifically and stabi...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章,评审

    doi:10.3390/ijms21020489

    authors: Liguori L,Monticelli M,Allocca M,Hay Mele B,Lukas J,Cubellis MV,Andreotti G

    更新日期:2020-01-13 00:00:00

  • Mitochondria and Calcium Homeostasis: Cisd2 as a Big Player in Cardiac Ageing.

    abstract::The ageing of human populations has become a problem throughout the world. In this context, increasing the healthy lifespan of individuals has become an important target for medical research and governments. Cardiac disease remains the leading cause of morbidity and mortality in ageing populations and results in signi...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章,评审

    doi:10.3390/ijms21239238

    authors: Yeh CH,Chou YJ,Kao CH,Tsai TF

    更新日期:2020-12-03 00:00:00

  • Differential Function of Endogenous and Exogenous Abscisic Acid during Bacterial Pattern-Induced Production of Reactive Oxygen Species in Arabidopsis.

    abstract::Abscisic acid (ABA) plays important roles in positively or negatively regulating plant disease resistance to pathogens. Here, we reassess the role of endogenous and exogenous ABA by using: 35S::ABA2, a previously reported transgenic Arabidopsis line with increased endogenous ABA levels; aba2-1, a previously reported A...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章

    doi:10.3390/ijms20102544

    authors: Tan L,Liu Q,Song Y,Zhou G,Luan L,Weng Q,He C

    更新日期:2019-05-23 00:00:00

  • The Effects of Early-Onset Pre-Eclampsia on Placental Creatine Metabolism in the Third Trimester.

    abstract::Creatine is a metabolite important for cellular energy homeostasis as it provides spatio-temporal adenosine triphosphate (ATP) buffering for cells with fluctuating energy demands. Here, we examined whether placental creatine metabolism was altered in cases of early-onset pre-eclampsia (PE), a condition known to cause ...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章

    doi:10.3390/ijms21030806

    authors: Ellery SJ,Murthi P,Gatta PAD,May AK,Davies-Tuck ML,Kowalski GM,Callahan DL,Bruce CR,Wallace EM,Walker DW,Dickinson H,Snow RJ

    更新日期:2020-01-26 00:00:00

  • Metabolomics of oxidative stress in recent studies of endogenous and exogenously administered intermediate metabolites.

    abstract::Aerobic metabolism occurs in a background of oxygen radicals and reactive oxygen species (ROS) that originate from the incomplete reduction of molecular oxygen in electron transfer reactions. The essential role of aerobic metabolism, the generation and consumption of ATP and other high energy phosphates, sustains a ba...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章,评审

    doi:10.3390/ijms12106469

    authors: Liu J,Litt L,Segal MR,Kelly MJ,Pelton JG,Kim M

    更新日期:2011-01-01 00:00:00

  • The EGFR-ERK/JNK-CCL20 Pathway in Scratched Keratinocytes May Underpin Koebnerization in Psoriasis Patients.

    abstract::Epidermal keratinocytes represent a rich source of C-C motif chemokine 20 (CCL20) and recruit CCR6+ interleukin (IL)-17A-producing T cells that are known to be pathogenic for psoriasis. A previous study revealed that scratch injury on keratinocytes upregulates CCL20 production, which is implicated in the Koebner pheno...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章

    doi:10.3390/ijms21020434

    authors: Furue K,Ito T,Tanaka Y,Hashimoto-Hachiya A,Takemura M,Murata M,Kido-Nakahara M,Tsuji G,Nakahara T,Furue M

    更新日期:2020-01-09 00:00:00

  • Salivary Small Extracellular Vesicles Associated miRNAs in Periodontal Status-A Pilot Study.

    abstract::This pilot study aims to investigate whether salivary small extracellular vesicle (sEV)-associated microRNAs could act as potential biomarkers for periodontal disease status. Twenty-nine participants (10 who were healthy, nine with gingivitis, 10 with stage III/IV periodontitis) were recruited and unstimulated whole s...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章

    doi:10.3390/ijms21082809

    authors: Han P,Bartold PM,Salomon C,Ivanovski S

    更新日期:2020-04-17 00:00:00

  • Protective Effects of Liquiritigenin against Citrinin-Triggered, Oxidative-Stress-Mediated Apoptosis and Disruption of Embryonic Development in Mouse Blastocysts.

    abstract::The mycotoxin citrinin (CTN), a natural contaminant in foodstuffs and animal feeds, exerts cytotoxic and genotoxic effects on various mammalian cells and embryos. A previous investigation by our group revealed potentially hazardous effects of CTN on mouse oocyte maturation and pre- and post-implantation embryo develop...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章

    doi:10.3390/ijms18122538

    authors: Huang CH,Chan WH

    更新日期:2017-11-27 00:00:00

  • In vitro models in biocompatibility assessment for biomedical-grade chitosan derivatives in wound management.

    abstract::One of the ultimate goals of wound healing research is to find effective healing techniques that utilize the regeneration of similar tissues. This involves the modification of various wound dressing biomaterials for proper wound management. The biopolymer chitosan (beta-1,4-D-glucosamine) has natural biocompatibility ...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章,评审

    doi:10.3390/ijms10031300

    authors: Keong LC,Halim AS

    更新日期:2009-03-01 00:00:00

  • Isolation and heterologous expression of a polygalacturonase produced by Fusarium oxysporum f. sp. cubense race 1 and 4.

    abstract::Fusarium wilt (Panama disease) caused by Fusarium oxysporum f. sp. cubense (FOC) represents a significant threat to banana (Musa spp.) production. Musa AAB is susceptible to Race 1 (FOC1) and Race 4 (FOC4), while Cavendish Musa AAA is found to be resistant to FOC1 but still susceptible to Race 4. A polygalacturonase (...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章

    doi:10.3390/ijms16047595

    authors: Dong Z,Wang Z

    更新日期:2015-04-03 00:00:00

  • The miRacle in Pancreatic Cancer by miRNAs: Tiny Angels or Devils in Disease Progression.

    abstract::Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with increasing incidence and high mortality. Surgical resection is the only potentially curative treatment of patients with PDAC. Because of the late presentation of the disease, about 20 percent of patients are candidates for this treatment. The ave...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章,评审

    doi:10.3390/ijms17060809

    authors: Hawa Z,Haque I,Ghosh A,Banerjee S,Harris L,Banerjee SK

    更新日期:2016-05-26 00:00:00

  • Crosstalk of the Brassinosteroid Signalosome with Phytohormonal and Stress Signaling Components Maintains a Balance between the Processes of Growth and Stress Tolerance.

    abstract::Brassinosteroids (BRs) are a class of phytohormones, which regulate various processes during plant life cycle. Intensive studies conducted with genetic, physiological and molecular approaches allowed identification of various components participating in the BR signaling-from the ligand perception, through cytoplasmic ...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章,评审

    doi:10.3390/ijms19092675

    authors: Gruszka D

    更新日期:2018-09-09 00:00:00

  • Establishing a Split Luciferase Assay for Proteinkinase G (PKG) Interaction Studies.

    abstract::Nitric oxide (NO/cyclic guanosine monophosphate (cGMP)-regulated cellular mechanisms are involved in a variety of (patho-) physiological processes. One of the main effector molecules in this system, proteinkinase G (PKG), serves as a molecular switch by phosphorylating different target proteins and thereby turning the...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章

    doi:10.3390/ijms19041180

    authors: Schramm A,Mueller-Thuemen P,Littmann T,Harloff M,Ozawa T,Schlossmann J

    更新日期:2018-04-12 00:00:00

  • The Expression of BNP, ET-1, and TGF-β1 in Myocardium of Rats with Ventricular Arrhythmias.

    abstract::Ventricular arrhythmia (VA) is a major component of sudden cardiac death (SCD). To investigate the expression of brain natriuretic peptide (BNP), endothelin-1 (ET-1), and transforming growth factor-beta 1 (TGF-β1) during VA, we established a rat model of VA induced by BaCl2 solution through a microinjector pump. PD142...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章

    doi:10.3390/ijms20235845

    authors: Tian M,Xiao Y,Xue J,Zhang Y,Jia Y,Luo X,Wang T,Zhu B,Cao Z

    更新日期:2019-11-21 00:00:00

  • Rack1 Mediates the Interaction of P-Glycoprotein with Anxa2 and Regulates Migration and Invasion of Multidrug-Resistant Breast Cancer Cells.

    abstract::The emergence of multidrug resistance is always associated with more rapid tumor recurrence and metastasis. P-glycoprotein (P-gp), which is a well-known multidrug-efflux transporter, confers enhanced invasion ability in drug-resistant cells. Previous studies have shown that P-gp probably exerts its tumor-promoting fun...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章

    doi:10.3390/ijms17101718

    authors: Yang Y,Wu N,Wang Z,Zhang F,Tian R,Ji W,Ren X,Niu R

    更新日期:2016-10-13 00:00:00

  • Goat's Milk Intake Prevents Obesity, Hepatic Steatosis and Insulin Resistance in Mice Fed A High-Fat Diet by Reducing Inflammatory Markers and Increasing Energy Expenditure and Mitochondrial Content in Skeletal Muscle.

    abstract::Goat's milk is a rich source of bioactive compounds (peptides, conjugated linoleic acid, short chain fatty acids, monounsaturated and polyunsaturated fatty acids, polyphenols such as phytoestrogens and minerals among others) that exert important health benefits. However, goat's milk composition depends on the type of ...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章

    doi:10.3390/ijms21155530

    authors: Delgadillo-Puga C,Noriega LG,Morales-Romero AM,Nieto-Camacho A,Granados-Portillo O,Rodríguez-López LA,Alemán G,Furuzawa-Carballeda J,Tovar AR,Cisneros-Zevallos L,Torre-Villalvazo I

    更新日期:2020-08-01 00:00:00

  • The Soluble Adenylyl Cyclase Inhibitor LRE1 Prevents Hepatic Ischemia/Reperfusion Damage Through Improvement of Mitochondrial Function.

    abstract::Hepatic ischemia/reperfusion (I/R) injury is a leading cause of organ dysfunction and failure in numerous pathological and surgical settings. At the core of this issue lies mitochondrial dysfunction. Hence, strategies that prime mitochondria towards damage resilience might prove applicable in a clinical setting. A pro...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章

    doi:10.3390/ijms21144896

    authors: Teodoro JS,Amorim JA,Machado IF,Castela AC,Steegborn C,Sinclair DA,Rolo AP,Palmeira CM

    更新日期:2020-07-11 00:00:00

  • Premature Activation of Immune Transcription Programs in Autoimmune-Predisposed Mouse Embryonic Stem Cells and Blastocysts.

    abstract::Autoimmune diabetes is a complex multifactorial disease with genetic and environmental factors playing pivotal roles. While many genes associated with the risk of diabetes have been identified to date, the mechanisms by which external triggers contribute to the genetic predisposition remain unclear. Here, we derived e...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章

    doi:10.3390/ijms21165743

    authors: Kirak O,Ke E,Yang KY,Schwarz A,Plate L,Nham A,Abadejos JR,Valencia A,Wiseman RL,Lui KO,Ku M

    更新日期:2020-08-11 00:00:00

  • Depression, GABA, and Age Correlate with Plasma Levels of Inflammatory Markers.

    abstract::Immunomodulation is increasingly being recognised as a part of mental diseases. Here, we examined whether levels of immunological protein markers changed with depression, age, or the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). An analysis of plasma samples from patients with a major depressive episode ...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章

    doi:10.3390/ijms20246172

    authors: Bhandage AK,Cunningham JL,Jin Z,Shen Q,Bongiovanni S,Korol SV,Syk M,Kamali-Moghaddam M,Ekselius L,Birnir B

    更新日期:2019-12-06 00:00:00

  • The Role of Cell Adhesion Molecule 1 (CADM1) in Cutaneous Malignancies.

    abstract::Cell adhesion ability is one of the components to establish cell organization and shows a great contribution to human body construction consisting of various types of cells mixture to orchestrate tissue specific function. The cell adhesion molecule 1 (CADM1) is a molecule of cell adhesion with multiple functions and h...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章,评审

    doi:10.3390/ijms21249732

    authors: Sawada Y,Mashima E,Saito-Sasaki N,Nakamura M

    更新日期:2020-12-20 00:00:00

  • Clinical Application of Targeted Next Generation Sequencing for Colorectal Cancers.

    abstract::Promising targeted therapy and personalized medicine are making molecular profiling of tumours a priority. For colorectal cancer (CRC) patients, international guidelines made RAS (KRAS and NRAS) status a prerequisite for the use of anti-epidermal growth factor receptor agents (anti-EGFR). Daily, new data emerge on the...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章,评审

    doi:10.3390/ijms17122117

    authors: Fontanges Q,De Mendonca R,Salmon I,Le Mercier M,D'Haene N

    更新日期:2016-12-16 00:00:00

  • Confocal Spectroscopy to Study Dimerization, Oligomerization and Aggregation of Proteins: A Practical Guide.

    abstract::Protein self-association is a key feature that can modulate the physiological role of proteins or lead to deleterious effects when uncontrolled. Protein oligomerization is a simple way to modify the activity of a protein, as the modulation of binding interfaces allows for self-activation or inhibition, or variation in...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章,评审

    doi:10.3390/ijms17050655

    authors: Gambin Y,Polinkovsky M,Francois B,Giles N,Bhumkar A,Sierecki E

    更新日期:2016-04-30 00:00:00

  • Adenosine Metabolism in the Cerebral Cortex from Several Mice Models during Aging.

    abstract::Adenosine is a neuromodulator that has been involved in aging and neurodegenerative diseases as Alzheimer's disease (AD). In the present work, we analyzed the possible modulation of purine metabolites, 5'nucleotidase (5'NT) and adenosine deaminase (ADA) activities, and adenosine monophosphate (AMP)-activated protein k...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章

    doi:10.3390/ijms21197300

    authors: Sánchez-Melgar A,Albasanz JL,Pallàs M,Martín M

    更新日期:2020-10-02 00:00:00

  • Royal Jelly Abrogates Cadmium-Induced Oxidative Challenge in Mouse Testes: Involvement of the Nrf2 Pathway.

    abstract::The current study examined the efficacy of royal jelly (RJ) against cadmium chloride (CdCl₂)-induced testicular dysfunction. A total of 28 Swiss male mice were allocated into four groups (n = 7), and are listed as follows: (1) the control group, who was intraperitoneally injected with physiological saline (0.9% NaCl) ...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章

    doi:10.3390/ijms19123979

    authors: Almeer RS,Soliman D,Kassab RB,AlBasher GI,Alarifi S,Alkahtani S,Ali D,Metwally D,Abdel Moneim AE

    更新日期:2018-12-10 00:00:00

  • The Convergence of the Hedgehog/Intein Fold in Different Protein Splicing Mechanisms.

    abstract::Protein splicing catalyzed by inteins utilizes many different combinations of amino-acid types at active sites. Inteins have been classified into three classes based on their characteristic sequences. We investigated the structural basis of the protein splicing mechanism of class 3 inteins by determining crystal struc...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章

    doi:10.3390/ijms21218367

    authors: Beyer HM,Virtanen SI,Aranko AS,Mikula KM,Lountos GT,Wlodawer A,Ollila OHS,Iwaï H

    更新日期:2020-11-07 00:00:00

  • UPR Signal Activation by Luminal Sensor Domains.

    abstract::The unfolded protein response (UPR) is a cell-signaling system that detects the accumulation of unfolded protein within the endoplasmic reticulum (ER) and initiates a number of cellular responses to restore ER homeostasis. The presence of unfolded protein is detected by the ER-luminal sensor domains of the three UPR-t...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章

    doi:10.3390/ijms14036454

    authors: Carrara M,Prischi F,Ali MM

    更新日期:2013-03-21 00:00:00

  • Role of cytokine signaling during nervous system development.

    abstract::Cytokines are signaling proteins that were first characterized as components of the immune response, but have been found to have pleiotropic effects in diverse aspects of body function in health and disease. They are secreted by numerous cells and are used extensively in intercellular communications to produce differe...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章,评审

    doi:10.3390/ijms140713931

    authors: Mousa A,Bakhiet M

    更新日期:2013-07-04 00:00:00

  • The Peculiar Glycolytic Pathway in Hyperthermophylic Archaea: Understanding Its Whims by Experimentation In Silico.

    abstract::Mathematical models are key to systems biology where they typically describe the topology and dynamics of biological networks, listing biochemical entities and their relationships with one another. Some (hyper)thermophilic Archaea contain an enzyme, called non-phosphorylating glyceraldehyde-3-phosphate dehydrogenase (...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章

    doi:10.3390/ijms18040876

    authors: Zhang Y,Kouril T,Snoep JL,Siebers B,Barberis M,Westerhoff HV

    更新日期:2017-04-20 00:00:00