The Warburg effect describes a pro-oncogenic metabolism switch that cancer cells take up more glucose than normal tissue, yet use less glucose for oxidative phosphorylation and favor glycolysis even in the presence of oxygen. However, how crucial this is for pathogenesis and disease progression in human cancers remains unknown. We approached these questions by examining whether tyrosine kinase signaling - commonly upregulated in tumors - regulates the Warburg effect to contribute to tumorigenesis and maintenance of the tumor. This hypothesis builds on our observation that a spectrum of key protein effectors of glycolysis and oxidative phosphorylation are regulated by tyrosine phosphorylation in leukemia cells expressing FGFR1 fusion tyrosine kinases, which are associated with 8p11 stem cell myeloproliferative disorder (MPD). These protein factors include pyruvate kinase M2 (fetal) isoform (PKM2), lactate dehydrogenase A (LDH-A), and pyruvate dehydrogenase kinase 1 (PDHK1), which work together to tightly regulate the metabolic pathways in cells. Thus, our overall hypothesis is that oncogenic FGFR1 promotes the Warburg effect and tumorigenesis by reprogramming cancer cell metabolism in an acute way via phosphorylation of PKM2, PDHK1 and LDH-A. In this proposal, we will use oncogenic FGFR1-associated 8p11 MPD expressing active FGFR1 fusion tyrosine kinases and lung cancer overexpressing FGFR1 as platforms.
Three Specific Aims are proposed: (1) To elucidate the molecular mechanisms by which FGFR1 reprograms cancer cell metabolism through direct phosphorylation of PKM2, PDHK1 and LDH-A;(2) To determine whether FGFR1-mediated phosphorylation of PKM2, PDHK1 and LDH-A promotes the metabolic switch to aerobic glycolysis from oxidative phosphorylation in cancer cells;(3) To determine whether FGFR1-mediated phosphorylation of PKM2, PDHK1 and LDH-A provides a metabolic advantage to tumor cell proliferation and tumor development. We will test the aforementioned "rescue" cell lines for dependence on glycolysis to proliferate and ability to form tumors in murine models of cancer.

Public Health Relevance

The Warburg effect describes a pro-oncogenic metabolism switch that cancer cells take up more glucose than normal tissue, yet use less glucose for oxidative phosphorylation and favor glycolysis even in the presence of oxygen. However, how crucial this is for pathogenesis and disease progression in human cancers remains unknown. Our overall hypothesis is that oncogenic FGFR1 programs cancer cell metabolism through tyrosine phosphorylation of metabolic enzymes including PKM2, PDHK1 and LDH-A to promote the Warburg effect and tumor growth.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA140515-03
Application #
8212152
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Spalholz, Barbara A
Project Start
2010-02-23
Project End
2014-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
3
Fiscal Year
2012
Total Cost
$315,144
Indirect Cost
$111,825
Name
Emory University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Fan, Jun; Shan, Changliang; Kang, Hee-Bum et al. (2014) Tyr phosphorylation of PDP1 toggles recruitment between ACAT1 and SIRT3 to regulate the pyruvate dehydrogenase complex. Mol Cell 53:534-48
Fan, Jun; Kang, Hee-Bum; Shan, Changliang et al. (2014) Tyr-301 phosphorylation inhibits pyruvate dehydrogenase by blocking substrate binding and promotes the Warburg effect. J Biol Chem 289:26533-41
Hitosugi, T; Chen, J (2014) Post-translational modifications and the Warburg effect. Oncogene 33:4279-85
Shan, Changliang; Elf, Shannon; Ji, Quanjiang et al. (2014) Lysine acetylation activates 6-phosphogluconate dehydrogenase to promote tumor growth. Mol Cell 55:552-65
Hitosugi, Taro; Zhou, Lu; Fan, Jun et al. (2013) Tyr26 phosphorylation of PGAM1 provides a metabolic advantage to tumours by stabilizing the active conformation. Nat Commun 4:1790
Fan, Jun; Hitosugi, Taro; Chung, Tae-Wook et al. (2011) Tyrosine phosphorylation of lactate dehydrogenase A is important for NADH/NAD(+) redox homeostasis in cancer cells. Mol Cell Biol 31:4938-50
Kang, Sumin; Chen, Jing (2011) Targeting RSK2 in human malignancies. Expert Opin Ther Targets 15:11-20