The Free Radical Cancer Biology Program (FRCBP) is unique to the HCCC and focuses on studying the biology of inherent differences in reductive and oxidative (redox) metabolism between cancer vs. normal cells. Research in the program is determining the role that redox reactions play in cancer phenotypic changes relevant to cell growth, differentiation, signal transduction, metastasis, functional molecular imaging, and therapy. A unifying goal of the program is to utilize a comprehensive basic science understanding of redox biology to develop novel biochemical rationales for improving cancer therapy. Three overlapping themes exist within the program. Theme 1: Understanding the role of redox biochemistry in regulation of genetic and epigenetic gene expression pathways relevant to cancer biology. Within this theme are research areas of focus exploring redox fluctuations and gene expression globally, as well as gene expression changes related of key redox sensitive molecules such as glutathione, thioredoxin, SOD, and AP2. Ttieme 2: Understanding the role of redox regulation in cell biology. Within this theme are research areas exploring the effects of redox on the cell cycle as well as invasion and metastasis. Ttieme 3: Exploring the role of oxidative stress in therapy outcomes. Within this theme are research areas exploring the role of manipulating oxidative stress to improve therapy as well as using imaging of oxidative metabolism as an approach to monitor and guide therapy. Major accomplishments of the FRCBP over the past funding period include findings that (a) cancer cells (relative to normal cells) produce increased steady-state levels of 02*'and H2O2 from mitochondrial metabolism that significantly contribute to differential susceptibility to clonogenic cell killing induced by glucose deprivation;(b) extracellular superoxide dismutase (EcSOD) inhibits invasion and metastasis;(c) expression of MnSOD governs the late production of reactive oxygen species, cell cycle check points, and transformation following radiation exposure;(d) that inhibitors of glucose and hydroperoxide metabolism can be used to enhance responses to radio-chemo-therapy by enhancing metabolic oxidative stress. The FRCBP consists of 18 members from 1 basic science department and 6 clinical departments and 2 colleges. Peer-reviewed, research funding for this program totals $3.9 million with over $2.0 million total costs from NCI. FRCBP members co-authored 237 publications. Of these publications, 20% were intraprogrammatic, 24% were interprogrammatic and 10% were both intra and interprogrammatic, for a total of 54% collaborative publications.

Public Health Relevance

It is becoming clear that metabolic oxidation/reduction reactions are altered in cancer vs. normal cells. The consensus is that cancer cells may exist in a chronic state of metabolic oxidative stress that may represent a significant underlying mechanism contributing to malignancy. A unifying goal of research in the FRCBP is to utilize a comprehensive understanding of cancer vs. normal cell redox biology to develop novel biochemical rationales for improving cancer therapy taking advantage fundamental differences in oxidative metabolism.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Center Core Grants (P30)
Project #
5P30CA086862-14
Application #
8640091
Study Section
Subcommittee G - Education (NCI)
Project Start
Project End
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
14
Fiscal Year
2014
Total Cost
$34,125
Indirect Cost
$28,739
Name
University of Iowa
Department
Type
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
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Machiela, Mitchell J; Lan, Qing; Slager, Susan L et al. (2016) Genetically predicted longer telomere length is associated with increased risk of B-cell lymphoma subtypes. Hum Mol Genet 25:1663-76
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Mambetsariev, Nurbek; Lin, Wai W; Stunz, Laura L et al. (2016) Nuclear TRAF3 is a negative regulator of CREB in B cells. Proc Natl Acad Sci U S A 113:1032-7
Brooks, Jennifer D; John, Esther M; Mellemkjaer, Lene et al. (2016) Body mass index, weight change, and risk of second primary breast cancer in the WECARE study: influence of estrogen receptor status of the first breast cancer. Cancer Med 5:3282-3291
Schroeder, Mary C; Chapman, Cole G; Nattinger, Matthew C et al. (2016) Variation in geographic access to chemotherapy by definitions of providers and service locations: a population-based observational study. BMC Health Serv Res 16:274
Wang, Bingxuan; Klaren, William D; Wels, Brian R et al. (2016) Dietary Manganese Modulates PCB126 Toxicity, Metal Status, and MnSOD in the Rat. Toxicol Sci 150:15-26
Craciun, Ioana; Fenner, Amanda M; Kerns, Robert J (2016) N-Arylacyl O-sulfonated aminoglycosides as novel inhibitors of human neutrophil elastase, cathepsin G and proteinase 3. Glycobiology 26:701-9
Safaeian, M; Robbins, H A; Berndt, S I et al. (2016) Risk of Colorectal Cancer After Solid Organ Transplantation in the United States. Am J Transplant 16:960-7
Klaren, William D; Gibson-Corley, Katherine N; Wels, Brian et al. (2016) Assessment of the Mitigative Capacity of Dietary Zinc on PCB126 Hepatotoxicity and the Contribution of Zinc to Toxicity. Chem Res Toxicol 29:851-9

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