We have been developing strategies to utilize nitric oxide (NO) in cancer treatment. In addition to the use of synthetic NO donors, we are researching the mechanisms that control the endogenous cellular production. We have recently discovered that inhibition of Nitric oxide synthase (NOS) given after chemotherapy or radiation treatment enhances tumor re-growth delay. Given that there are a number of clinically available NOS inhibitors this could have potential clinical applications. We have recently characterized the NO levels that are required to activate and stabilize key proteins involved in carcinogenesis, p53, ERK and HIF1-alpha. Our recent discover that NOS-2 and COX-2 are strong predictor of poor prognosis in ER negative cancer. In patient cohort we have found that 94% of the deseased had high NOS2 in ER- patients. We have been exploring the molecular mechanisms that elucidate pathways that link these biomarkers. We have found that NO has two effect: one it activates key pathways, beta-catenin, NFkappa, AP-1 and ETS. These pathways lead to increase proliferation, migration and cancer stem cell markers. These findings have provided new models to develop compounds that target this particular aggressive cancer type describe in project 3 and 4. One of the unique aspect is that NO can induce many markers that associated with poor prognosis in breast cancer. However, activation of the pathways are not enough, there has to be inhibition of tumor supressor proteins. We have found that BRCA1 and PP2A are both inhibited by NO. This molecular profile points to a unique mechanism that suggest NO and NOS-2 are complete protumorigenic agent with implications in breast, colon, liver, brain, prostate, stomach and pancreatic cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIASC007281-20
Application #
8763688
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
20
Fiscal Year
2013
Total Cost
$402,444
Indirect Cost
Name
National Cancer Institute Division of Clinical Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Basudhar, Debashree; Ridnour, Lisa A; Cheng, Robert et al. (2016) Biological signaling by small inorganic molecules. Coord Chem Rev 306:708-723
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Switzer, Christopher H; Cheng, Robert Y-S; Ridnour, Lisa A et al. (2012) Ets-1 is a transcriptional mediator of oncogenic nitric oxide signaling in estrogen receptor-negative breast cancer. Breast Cancer Res 14:R125
Moody, Terry W; Osefo, Nauramy; Nuche-Berenguer, Bernardo et al. (2012) Pituitary adenylate cyclase-activating polypeptide causes tyrosine phosphorylation of the epidermal growth factor receptor in lung cancer cells. J Pharmacol Exp Ther 341:873-81
Fukuto, Jon M; Carrington, Samantha J; Tantillo, Dean J et al. (2012) Small molecule signaling agents: the integrated chemistry and biochemistry of nitrogen oxides, oxides of carbon, dioxygen, hydrogen sulfide, and their derived species. Chem Res Toxicol 25:769-93
Wink, David A; Hines, Harry B; Cheng, Robert Y S et al. (2011) Nitric oxide and redox mechanisms in the immune response. J Leukoc Biol 89:873-91

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