Begell House Inc.
Onco Therapeutics
OT
2694-4642
3
2
2012
Preface: First International Conference on Nitrosylation in Oncology and Immunology; Speakers' Presentations
0
10.1615/ForumImmunDisTher.2012006096
Benjamin
Bonavida
Department of Microbiology, Immunology, &
Molecular Genetics, David Geffen School of Medicine at UCLA, Johnson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA 90025-1747, USA
Jean-Francois
Jeannin
EPHE Tumor Immunology and Immunotherapy, Laboratory, University of Burgundy, Dijon, France
Thiol Modification By Pharmacologically Active Agents of the Diazeniumdiolate Class
91-95
10.1615/ForumImmunDisTher.2012006334
Anna E.
Maciag
Basic Science Program, SAIC-Frederick, Inc., Frederick, Maryland
Ryan J.
Holland
Chemical Biology Laboratory, Frederick National Laboratory for Cancer Research, Frederick, Maryland
Joseph E.
Saavedra
Basic Science Program, SAIC-Frederick, Inc., Frederick, Maryland
Harinath
Chakrapani
Indian Institute of Science Education and Research, Pune, India
Paul J.
Shami
Department of Medicine, Division of Hematology and Hematologic Malignancies, Huntsman Cancer Institute, 2000 Circle of Hope, Suite 2100, University of Utah, Salt Lake City
Larry K.
Keefer
Chemical Biology Laboratory, Frederick National Laboratory for Cancer Research, Frederick, Maryland
thiol
nitric oxide
diazeniumdiolate
Promising drug candidates of the diazeniumdiolate (NONOate) chemical family include several types of thiol modification among their mechanisms of action: 1) drugs designed to release nitric oxide (NO) on reaction with the thiol group of glutathione (GSH) arylate the GSH, a step that removes reducing equivalents from the cell; (2) a similar reaction of the drug with the thiol group of a protein changes its structure, leading to potentially impaired function and cell death; (3) the NO generated as a byproduct in the above reactions can undergo oxidation, leading to S-nitrosylation and S-glutathionylation; and (4) diazeniumdiolates can also generate nitroxyl, which reacts with thiol groups to form disulfides or sulfinamides.
Nitric Oxide−Releasing Hybrid Drugs Target Cellular Processes Through S-Nitrosylation
97-108
10.1615/ForumImmunDisTher.2012006099
Khosrow
Kashfi
Department of Molecular, Cellular and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, 160 Convent Avenue, New York, NY 10031, USA; Graduate Program in Biology, City University of New York Graduate Center, New York, NY, USA
nitric oxide
NF-kÂ
B-catenin
caspase-3
NSAIDs
NO-NSAIDs
NONO-NSAIDs
JS-K
S-nitrosylation
colon cancer
chemoprevention
Nitric oxide (NO)−releasing agents such as JS-K and NO−releasing hybrids such as NO− and NONO−nonsteroidal anti-inflammatory drugs are novel agents with great potential for controlling cancer. Although studied extensively, a key question pertaining to their molecular targets and mechanism of action remains unclear: the role of NO in the overall biological effect of these agents. It has been shown that NO can directly modify sulfhydryl residues of proteins through S-nitrosylation and induce apoptosis. We showed that 3 structurally diverse NO−nonsteroidal anti-inflammatory drugs S-nitrosylated nuclear factor-κ p65 in vitro and in vivo and also showed that these agents S-nitrosylated caspase-3 in vivo. JS-K reduced nuclear β-catenin and cyclin D1 protein levels without affecting cytosolic β-catenin expression. On the basis of a time course study, S-nitrsolyation of nuclear β-catenin was determined to precede its degradation. These data provide a mechanistic role for NO and a rationale for the chemopreventive effects of these novel agents.
Neutral Sphingomyelinase 2 Is an Important Mediator of Cellular Stress Responses
109-115
10.1615/ForumImmunDisTher.2012006205
Bei Lei
Sun
Department of Chemistry and Biochemistry, University of Windsor, Windsor, Ontario, Canada
Bulent
Mutus
Department of Chemistry and Biochemistry, University of Windsor, Windsor, Ontario, Canada
neutral sphingomyelinase 2
ceramide
cellular stress response
Neutral sphingomyelinase 2 (NSMase 2) belongs to the class of enzymes (EC.3.1.4.12) that catalyzes the hydrolysis of sphingomyelin to form ceramide and phosphocholine. Recent studies have shown that the expression level and activity of NSMase 2 is altered upon exposure to a number of stressors, including oxidative stress, endoplasmic reticulum stress, tumor necrosis factor a, and anticancer drugs. This altered activity directly translates into changes in ceramide levels, which ultimately lead to the appropriate cellular response, such as growth arrest or apoptosis. Overall, this implies that NSMase 2 plays an important role in mediating the proper stress response, and inappropriate activation or inhibition of NSMase 2 could contribute to the development of pathological conditions such as cancer and endothelial dysfunction. In this review, we focus on recent findings in the field of NSMase 2−mediated cellular stress response.
S-Nitrosation Mediates Multiple Pathways That Lead to Tumor Progression in Estrogen Receptor−Negative Breast Cancer
117-124
10.1615/ForumImmunDisTher.2012006108
Christopher H.
Switzer
Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
Lisa A.
Ridnour
Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
Robert
Cheng
Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
Julie
Heinecke
Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
Amy
Burke
Prostate Cancer Institute, National University of Ireland Galway, Galway, Ireland
Sharon
Glynn
Prostate Cancer Institute, National University of Ireland Galway, Galway, Ireland
Stefan
Ambs
laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
David A.
Wink
Cancer and Inflammation Program, Laboratory of Cancer Immunometabolism, National Cancer Institute, Frederick, Maryland
nitric oxide
cancer
nitrosative stress
S-nitrosylation
Chronic inflammation within the tumor microenvironment is a major driver of tumor progression and poor prognosis. Inducible nitric oxide synthase (NOS2) is present in numerous solid tumors. Estrogen receptor−negative (ER-) patients with high expression of tumor NOS2 have a poorer outcome than patients with low expression of NOS2. Furthermore, expression of NOS2 is associated with the basal-like breast cancer phenotype. Using an in vitro model, we have found that nitrosation of critical thiols and nitration of tyrosines lead to the activation of membrane receptors such as epithelial growth factor receptor, Src, Ras, and CD63. These nitric oxide−mediated events in itiate oncogenic signaling pathways such as PI3K/Akt, Ras/ERK, β-catenin, nuclear factor-κÂ, and AP-1. These data suggest that NOS2 can serve as a major "nonmutatational driver" of ER- breast cancer.
Inhibition of Epithelial-to-Mesenchymal Transition (EMT) in Cancer by Nitric Oxide: Pivotal Roles of Nitrosylation of NF-κB, YY1 and Snail
125-133
10.1615/ForumImmunDisTher.2012006065
Benjamin
Bonavida
Department of Microbiology, Immunology, &
Molecular Genetics, David Geffen School of Medicine at UCLA, Johnson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA 90025-1747, USA
Stavroula
Baritaki
Center for Systems Biomedicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
nitric oxide
epithelial-to-mesenchymal transition (EMT)
Yin Yang 1
Raf kinase inhibitor protein
metastasis
Treatment of cancer cell lines with high levels of nitric oxide (NO) via NO donors, such as DETANONOate, inhibits cell growth and survival pathways and sensitizes resistant tumor cells to apoptosis by chemoimmunotherapeutic drugs. In addition, we recently have reported that NO also inhibits the epithelial-to-mesenchymal transition (EMT) phenotype in metastatic cancer cell lines via dysregulation of the nuclear factor (NF)-κB/Snail/Yin Yang 1 (YY1)/Raf kinase inhibitor protein circuitry. The mechanism underlying NO-mediated dysregulation of this circuit was investigated, namely, NO-mediated inhibition of the activity of the transcription factors NF-κB, Snail, and YY1. We hypothesized that one mechanism of NO-mediated inhibition may invoke the NO-induced S-nitrosylation of these transcription factors. We demonstrate in metastatic and EMT+ human prostate carcinoma cell lines that treatment with NO results in the S-nitrosylation of NF-κB (p50), Snail, and YY1 and inhibits their activities, resulting in the reversal of the EMT phenotype into a mesenchymal -to-epithelial transition phenotype. These findings suggest that NO donors may be potential therapeutic agents in both the reversal of resistance and the inhibition of EMT and metastasis.
Ras Denitrosylation in Human Lung Cancer
135-139
10.1615/ForumImmunDisTher.2012006133
Benjamin
Gaston
University of Virginia School of Medicine, Department of Pediatrics, Charlottesville, Virginia
Nadzeya
Marozkina
University of Virginia School of Medicine, Department of Pediatrics, Charlottesville, Virginia
S-nitrosylation
S-nitrosothiol
nitrosative stress
S-nitrosylation and denitrosylation are regulated signaling reactions. They are also relevant to the toxicology of nitrogen oxides. S-nitrosoglutathione (GSNO) reductase is an important denitrosylating enzyme, acting through intermediate GSNO formation from S-nitrosylated proteins and from reduced glutathione. It also serves to protect cells from excessive nitrosative stress. Endothelial nitric oxide synthase (NOS) activation downstream of oncogenic Ras causes S-nitrosylation of wild-type Ras that is necessary for oncogenesis. GSNO reductase serves as a Ras denitrosylase, protecting against oncogenesis. Exposure to exogenous nitric oxide, such as that present in high concentrations in cigarette smoke, also S-nitrosylates Ras. GSNO reductase expression and activity are decreased in various types of lung cancer. Taken together, these data suggest that GSNO reductase expression is important for protection against the tumorigenic effects, mediated by Ras S-nitrosylation, of both overactivation of endothelial NOS and chronic exposure to smoke.
Nitrosothiol Signaling in Anoikis Resistance and Cancer Metastasis
141-154
10.1615/ForumImmunDisTher.2012006115
Sudjit
Luanpitpong
Department of Pharmaceutical Sciences, Hampton University, Hampton, Virginia
Anand Krishnan V.
Iyer
Department of Pharmaceutical Sciences, School of Pharmacy, Hampton University, Hampton, Virginia
Neelam
Azad
Department of Pharmaceutical Sciences, School of Pharmacy, Hampton University, Hampton, Virginia
Liying
Wang
Pathology and Physiology Research Branch, National Institute for Occupational Safety and Health, Morgantown, West Virginia
Yon
Rojanasakul
Department of Pharmaceutical Sciences, Hampton University, Hampton, Virginia; Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia
nitric oxide
S-nitrosylation
cancer
metastasis
anoikis
invasion
Nitric oxide (NO) has been widely recognized as an important cell-signaling molecule that regulates various physiological and pathological processes. S-nitrosylation, or covalent attachment of NO to protein sulfhydryl groups, is a key mechanism by which NO regulates protein functions and cellular processes. In this article we discuss the various roles of NO and protein nitrosylation in cancer development, with a focus on cell invasion and anoikis resistance, both of which are key determinants of cancer metastasis. We specially address some of the mechanisms by which NO-mediated S-nitrosylation modulates substrates that have putative effects on key steps of metastasis. We propose that nitrosothiol signaling is a key regulatory mechanism common to several pathways involved in cancer progression and metastasis, and identifying such a mechanism will improve our understanding of the disease process and aid in the development of novel anticancer therapeutics.
Chemoprevention of Colon Cancer by iNOS-Selective Inhibitors
155-167
10.1615/ForumImmunDisTher.2012006186
Naveena B.
Janakiram
Center for Cancer Prevention and Drug Development, Medical Oncology, Department of Medicine, PCS Oklahoma Cancer Center, University of Oklahoma Health Sciences, Oklahoma City, Oklahoma
Chinthalapally V.
Rao
Center for Cancer Prevention and Drug Development, Medical Oncology, Department of Medicine, PCS Oklahoma Cancer Center, University of Oklahoma Health Sciences, Oklahoma City, Oklahoma
nitric oxide
angiogenesis
chemoprevention
iNOS-selective inhibitors
colorectal cancer
Nitric oxide (NO) is a short-lived pleiotropic regulator and is required for numerous pathophysiological functions, including macrophage-mediated immunity and cancer. It is a highly reactive free radical produced from L-arginine by different isoforms of NO synthases (NOSs). Sustained induction of inducible NOS (iNOS) during chronic inflammatory conditions leads to the formation of reactive intermediates of NO, which are mutagenic and cause DNA damage or impairment of DNA repair, alter cell signaling, and promote proinflammatory and angiogenic properties of the cell, thus contributing to carcinogenesis. Besides its well-established role in inflammation, increased expression of iNOS has been observed in colorectal tumors and other cancers. NO-related signaling pathways involved in colon tumorigenesis seem to progress through stimulation of proinflammatory cytokines and via posttranslational protein modifications of important antiapoptotic molecules in the tumors. NO can stimulate and enhance tumor cell proliferation by promoting invasive, angiogenic, and migratory activities. In contrast, studies also suggest that high levels of NO may be protective against tumor growth by inducing tumor cell death. However, a number of in vitro studies and particularly experimental animal data support the notion that NO and its reactive metabolite peroxynitrite stimulate cyclooxygenase-2 activity, leading to generation of prostaglandins that enhance tumor growth. These prostaglandins further augment tumor promotion and invasive properties of tumor cells. Hence, selective inhibitors of iNOS and combination strategies to inhibit both iNOS and cyclooxygenase-2 may have a preventive role in colon cancer.
A Role for Nitric Oxide and for Nitric Oxide Synthases in Tumor Biology
169-182
10.1615/ForumImmunDisTher.2012006134
Graciele A.
de Oliveira
Departamento de Bioquimica/Biologia Molecular, Centro de Terapia Celular e Molecular, Universidade Federal de Sao Paulo, Campus Sao Paulo, Sao Paulo, Brazil
Heloisa
Rosa
Departamento de Bioquimica/Biologia Molecular, Centro de Terapia Celular e Molecular, Universidade Federal de Sao Paulo, Campus Sao Paulo, Sao Paulo, Brazil
Adriana Karla C.A.
Reis
Departamento de Ciencias Exatas e da Terra, Universidade Federal de Sao Paulo, Campus Diadema, Sao Paulo, Brazil
Arnold
Stern
Department of Pharmacology, New York University School of Medicine, New York, NY
Hugo P.
Monteiro
Departamento de Bioquimica/Biologia Molecular, Centro de Terapia Celular e Molecular, Universidade Federal de Sao Paulo, Campus Sao Paulo, Sao Paulo, Brazil
nitric oxide
nitric oxide synthases
S-nitrosylation
tyrosine phosphorylation
protein kinases
protein phosphatases
S-nitrosothiols
redox signaling
cancer biology
The dual role of nitric oxide in cancer biology is discussed here through the perspective of our work on nitric oxide−mediated signaling events. The nitric oxide-stimulated Src-FAK and Ras-ERK1/2 mitogen-activated protein kinases (MAPKs) oncogenic signaling pathways are discussed, highlighting the cross-talk between 2 major posttranslational modifications: protein phosphorylation and protein S-nitrosylation. In addition, we discuss the importance of nitric oxide synthases in cancer biology, focusing on the roles of endothelial nitric oxide synthase and arginase 2 in human thyroid tumor progression. A direct relationship between the expression levels of both enzymes was found in human follicular thyroid carcinoma. Finally, the antioncogenic, proapoptotic actions of nitric oxide based on its anti-adhesive properties are presented and discussed.
A Conspectus of Cellular Mechanisms of Nitrosothiol Formation from Nitric Oxide
183-191
10.1615/ForumImmunDisTher.2012006372
Qian
Li
Center for Free Radical Biology Departments of Anesthesiology, University of Alabama Birmingham, Birmingham, AL 35294
Jack R.
Lancaster, jr.
Center for Free Radical Biology Departments of Anesthesiology, University of Alabama Birmingham, Birmingham, AL 35294; Cell, Developmental, and Integrative Biology, and Environmental Health Sciences University of Alabama Birmingham, Birmingham, AL 35294
nitric oxide; nitrogen monoxide; nitrosation; nitrosothiol; dinitrosyliron complexes; cytochrome c
Although chemical mechanisms for the formation of nitrosothiol from ·NO have been studied extensively "in the test tube", surprisingly little is known regarding the mechanism(s) of how nitrosothiols are formed in vivo. This lack of understanding has hampered more general acceptance of the concept of cysteine nitrosothiol formation as a generally applicable, regulated, and functionally significant protein posttranslational modification (as opposed to multiple other ·NO-induced thiol modifications). Here we provide a brief overview/summary of the cellular formation of nitrosothiols from ·NO via two possible mechanisms involving oxygen or transition metals.