The JAK2V617F oncogene requires expression of inducible phosphofructokinase/fructose-bisphosphatase 3 for cell growth and increased metabolic activity
Open Access
- 23 August 2011
- journal article
- research article
- Published by Springer Science and Business Media LLC in Leukemia
- Vol. 26 (3), 481-489
- https://doi.org/10.1038/leu.2011.225
Abstract
Myeloproliferative neoplasms are characterized by overproduction of myeloid lineage cells with frequent acquisition of oncogenic JAK2V617F kinase mutations. The molecular mechanisms that regulate energy requirements in these diseases are poorly understood. Transformed cells tend to rely on fermentation instead of more efficient oxidative phosphorylation for energy production. Our data in JAK2V617F-transformed cells show that growth and metabolic activity were strictly dependent on the presence of glucose. Uptake of glucose and cell surface expression of the glucose transporter Glut1 required the oncogenic tyrosine kinase. Importantly, JAK2V617F as well as active STAT5 increased the expression of the inducible rate-limiting enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), which controls glycolytic flux through 6-phosphofructo-1-kinase. PFKFB3 was required for JAK2V617F-dependent lactate production, oxidative metabolic activity and glucose uptake. Targeted knockdown of PFKFB3 also limited cell growth under normoxic and hypoxic conditions and blocked in vivo tumor formation in mice. Overall, these data suggest that inducible PFKFB3 is required for increased growth, metabolic activity and is regulated through active JAK2 and STAT5. Novel therapies that specifically block PFKFB3 activity or expression would, therefore, be expected to inhibit JAK2/STAT5-dependent malignancies and related cancers.Keywords
This publication has 35 references indexed in Scilit:
- BCR-ABL promotes the frequency of mutagenic single-strand annealing DNA repairPublished by American Society of Hematology ,2009
- Myeloproliferative disordersBlood, 2008
- The Jak2V617F oncogene associated with myeloproliferative diseases requires a functional FERM domain for transformation and for expression of the Myc and Pim proto-oncogenesBlood, 2008
- Interpretation of cytokine signaling through the transcription factors STAT5A and STAT5BGenes & Development, 2008
- The interplay between MYC and HIF in cancerNature Reviews Cancer, 2008
- Small-molecule inhibition of 6-phosphofructo-2-kinase activity suppresses glycolytic flux and tumor growthMolecular Cancer Therapeutics, 2008
- HIF and c-Myc: Sibling Rivals for Control of Cancer Cell Metabolism and ProliferationCancer Cell, 2007
- Phosphorylation of the 6-Phosphofructo-2-Kinase/Fructose 2,6-Bisphosphatase/PFKFB3 Family of Glycolytic Regulators in Human CancerClinical Cancer Research, 2005
- Targeted disruption of inducible 6-phosphofructo-2-kinase results in embryonic lethalityBiochemical and Biophysical Research Communications, 2005
- A Kinetic Study of Pyrophosphate: Fructose‐6‐Phosphate Phosphotransferase from Potato TubersEuropean Journal of Biochemistry, 1982