Despite major advances in diagnosis and therapy there have been no improvements in the survival of patients with primary malignant brain tumors. Gliomas are the most common primary brain tumors in humans and glioblastoma multiforme (GBM) is the most aggressive of these tumors. GBMs are highly resistant to radiation and chemotherapy and nearly all patients with GBM die of their disease with a median survival of one year. In addition to genetic alterations, tumor hypoxia may play a role in the malignant progression of gliomas. This may be because tumor hypoxia induces the expression of angiogenic and cell survival-promoting cytokines and enhances the glycolytic capability of cancer cells. Hypoxia activates gene expression via the transcription factor HIF-1 which can also be turned on by certain growth factors. We have identified a novel biochemical pathway by which glycolytic metabolites such as lactate and pyruvate stabilize HIF-1alpha protein levels independently of hypoxia. Since the majority of hypoxia-independent activators of HIF- 1 also enhance glycolysis, this pathway may provide a mechanism accounting for their actions. Our recent discovery of autocrine erythropoietin signaling in human cancer also points to a major role for hypoxia in enhancing the survival of cancer cells via mechanisms not previously appreciated. The research proposed here will explore the relationship between hypoxia, altered gene expression, cell metabolism and cell survival. Our hypothesis is that hypoxia-induced changes in the ,qlycolytic metabolism of cancer cells results in the self-sustaining activation of HIF-1alpha regulated genes, even in the absence of persisting hypoxia. We will test our hypothesis by pursuing four aims:
Specific Aim #1 : Determine the mechanism by which glycolytic metabolites regulate HIF-1alpha protein stability.
Specific Aim #2 : Test the hypothesis that hypoxia-independent activators of HIF-1alpha act via regulation of glycolysis.
Specific Aim #3 : Determine whether hypoxic selection of treatment-resistant glioma cells results from the self-sustaining activation of HIF-1alpha regulated genes.
Specific Aim #4 : Test the hypothesis that erythropoietin signaling plays a prominent role in the hypoxia-induced selection of glioma cells with diminished apoptotic potential.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS037814-06
Application #
6773216
Study Section
Special Emphasis Panel (ZRG1-BDCN-3 (01))
Program Officer
Finkelstein, Robert
Project Start
1998-07-25
Project End
2006-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
6
Fiscal Year
2004
Total Cost
$317,846
Indirect Cost
Name
Henry M. Jackson Fdn for the Adv Mil/Med
Department
Type
DUNS #
144676566
City
Rockville
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
Xing, Guoqiang; Qualls, Clifford; Huicho, Luis et al. (2008) Adaptation and mal-adaptation to ambient hypoxia;Andean, Ethiopian and Himalayan patterns. PLoS One 3:e2342
Huicho, Luis; Xing, Guoqiang; Qualls, Clifford et al. (2008) Abnormal energy regulation in early life: childhood gene expression may predict subsequent chronic mountain sickness. BMC Pediatr 8:47
Mohyeldin, Ahmed; Dalgard, Clifton L; Lu, Huasheng et al. (2007) Survival and invasiveness of astrocytomas promoted by erythropoietin. J Neurosurg 106:338-50
Lu, Huasheng; Dalgard, Clifton L; Mohyeldin, Ahmed et al. (2005) Reversible inactivation of HIF-1 prolyl hydroxylases allows cell metabolism to control basal HIF-1. J Biol Chem 280:41928-39
Dalgard, Clifton Lee; Lu, Huasheng; Mohyeldin, Ahmed et al. (2004) Endogenous 2-oxoacids differentially regulate expression of oxygen sensors. Biochem J 380:419-24
Watson, William D; Facchina, Stephen L; Grimaldi, Maurizio et al. (2003) Sarco-endoplasmic reticulum Ca2+ ATPase (SERCA) inhibitors identify a novel calcium pool in the central nervous system. J Neurochem 87:30-43
Grimaldi, Maurizio; Maratos, Marina; Verma, Ajay (2003) Transient receptor potential channel activation causes a novel form of [Ca 2+]I oscillations and is not involved in capacitative Ca 2+ entry in glial cells. J Neurosci 23:4737-45
Acs, Geza; Zhang, Paul J; McGrath, Cindy M et al. (2003) Hypoxia-inducible erythropoietin signaling in squamous dysplasia and squamous cell carcinoma of the uterine cervix and its potential role in cervical carcinogenesis and tumor progression. Am J Pathol 162:1789-806
Lu, Huasheng; Forbes, Robert A; Verma, Ajay (2002) Hypoxia-inducible factor 1 activation by aerobic glycolysis implicates the Warburg effect in carcinogenesis. J Biol Chem 277:23111-5

Showing the most recent 10 out of 11 publications