Several recent studies have demonstrated that ionizing radiation activates a metabolic process resulting in the transient generation of reactive oxygen (ROS). The underlying mechanism for this amplification and signaling mechanism of cytoplasmic ionization events appears to involve a Ca2+ dependent signal propagated from one mitochondria to another within a cell. Temporally coincident is the activation of a constitutive, Ca2+ dependent nitric oxide synthase (NOS*). It is proposed that the radiation-induced activation of NOS is a mechanism that (1) limits the amount of cytotoxic, mutagenic ROS (02-/H202) formed after radiation; and (2) activates signal transduction pathways involved in cell growth regulation. Because of its unique physiochemical properties, the enhanced NO. generation after irradiation also provides a mechanism for the intracellular and intercellular propagation within a tissue of a signal generated by an ionization event that has occurred in a single cell. To test this proposal, there are two specific aims: ? ? Determine whether modulation of NOS activity by molecular and pharmacological means enhances radiation-induced cell killing and/or mutagenesis that in turn can be reduced by over expression of superoxide dismutase (SOD) or treating cells with SOD mimetics. Determine whether manipulation of NOS activity modulates radiation-induced ROS generation measured as 02 ? ? Test (a) whether manipulation of the NO-/sGC/PKG signal transduction pathway alters cellular radiosensitivity; (b) the relationships between radiation-stimulated sGC/PKG and downstream consequences including transcriptional activation of c-fos and p21 Waf1/Cip1 and activation of members of the MAPK family and (c) whether radiation-stimulated transient S-nitrosylation and inhibition of cytosolic and nuclear protein tyrosine phosphatases (PIP) are involved in cellular responses to radiation (SHP-2, SHP-1 and cdc25).

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA090881-03
Application #
6757956
Study Section
Radiation Study Section (RAD)
Program Officer
Pelroy, Richard
Project Start
2002-07-10
Project End
2006-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
3
Fiscal Year
2004
Total Cost
$267,375
Indirect Cost
Name
Virginia Commonwealth University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
Yakovlev, Vasily A (2015) Role of nitric oxide in the radiation-induced bystander effect. Redox Biol 6:396-400
Rabender, Christopher S; Alam, Asim; Sundaresan, Gobalakrishnan et al. (2015) The Role of Nitric Oxide Synthase Uncoupling in Tumor Progression. Mol Cancer Res 13:1034-43
Alam, Asim; Mukhopadhyay, Nitai D; Ning, Yi et al. (2015) A Preliminary Study on Racial Differences in HMOX1, NFE2L2, and TGF?1 Gene Polymorphisms and Radiation-Induced Late Normal Tissue Toxicity. Int J Radiat Oncol Biol Phys 93:436-43
Cardnell, Robert J G; Rabender, Christopher S; Ross, Gracious R et al. (2013) Sepiapterin ameliorates chemically induced murine colitis and azoxymethane-induced colon cancer. J Pharmacol Exp Ther 347:117-25
Yakovlev, Vasily A (2013) Nitric oxide-dependent downregulation of BRCA1 expression promotes genetic instability. Cancer Res 73:706-15
Zhang, Qifang; Raje, Vidisha; Yakovlev, Vasily A et al. (2013) Mitochondrial localized Stat3 promotes breast cancer growth via phosphorylation of serine 727. J Biol Chem 288:31280-8
Guo, Chunqing; Yi, Huanfa; Yu, Xiaofei et al. (2012) In situ vaccination with CD204 gene-silenced dendritic cell, not unmodified dendritic cell, enhances radiation therapy of prostate cancer. Mol Cancer Ther 11:2331-41
Bayden, Alexander S; Yakovlev, Vasily A; Graves, Paul R et al. (2011) Factors influencing protein tyrosine nitration--structure-based predictive models. Free Radic Biol Med 50:749-62
Cardnell, Robert J G; Mikkelsen, Ross B (2011) Nitric oxide synthase inhibition enhances the antitumor effect of radiation in the treatment of squamous carcinoma xenografts. PLoS One 6:e20147
Yakovlev, Vasily A; Mikkelsen, Ross B (2010) Protein tyrosine nitration in cellular signal transduction pathways. J Recept Signal Transduct Res 30:420-9

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