Tumor hypoxia plays an important role in the malignant progression and clinical outcome of solid cancers. This may be because tumor hypoxia induces the expression of angiogenic and cell survival-promoting cytokines and enhances invasiveness of cancer cells. We have recently provided evidence for hypoxia-inducible autocrine erythropoietin (Epo) signaling in the malignant progression of several human cancers including breast, cervical, endometrial, and head/neck cancer. Epo and the Epo receptor (EpoR), are among many genes upregulated by tumor hypoxia, and Epo signaling promotes invasiveness of head/neck cancer cells. The transcription factor known as hypoxia-inducible factor-1 (HIF-1) is critically involved in tumor hypoxia induced adaptations. Expression of HIF-1 alpha, the key hypoxia-regulated subunit of HIF-1, is highly up-regulated in a variety of human cancers and is strongly correlated with tumor grade, angiogenesis, and adverse clinical outcome. We have discovered a novel hypoxia-independent mechanism that increases HIF-1 alpha levels in cancer cells via the glycolytic metabolite pyruvate. We have also discovered that ascorbate and specific amino acids can reverse this process. The goal of this application is to determine whether lowering basal HIF-1 expression by using ascorbate and amino acids can reduce HIF-induced gene expression, Epo signaling, and invasiveness of human head/neck cancer cells. We will also determine whether in vivo treatment with ascorbate and amino acids can lower HIF-1 expression, Epo and EpoR expression, and tumor growth in a human head/neck cancer xenograft model. We believe that our studies will yield novel and safe therapeutic options for cancer patients. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA113506-02
Application #
7229948
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Perloff, Marjorie
Project Start
2006-01-26
Project End
2007-12-31
Budget Start
2007-03-05
Budget End
2007-12-31
Support Year
2
Fiscal Year
2007
Total Cost
$111,801
Indirect Cost
Name
Henry M. Jackson Fdn for the Adv Mil/Med
Department
Type
DUNS #
144676566
City
Bethesda
State
MD
Country
United States
Zip Code
20817
Halim, Nader D; Mcfate, Thomas; Mohyeldin, Ahmed et al. (2010) Phosphorylation status of pyruvate dehydrogenase distinguishes metabolic phenotypes of cultured rat brain astrocytes and neurons. Glia 58:1168-76
McFate, Thomas; Mohyeldin, Ahmed; Lu, Huasheng et al. (2008) Pyruvate dehydrogenase complex activity controls metabolic and malignant phenotype in cancer cells. J Biol Chem 283:22700-8