The JAK2V617F oncogene requires expression of inducible phosphofructokinase/fructose-bisphosphatase 3 for cell growth and increased metabolic activity Journal Article

   

Authors:	Reddy, M. M.; Fernandes, M. S.; Deshpande, A.; Weisberg, E.; Inguilizian, H. V.; Abdel-Wahab, O.; Kung, A. L.; Levine, R. L.; Griffin, J. D.; Sattler, M.
Article Title:	The JAK2V617F oncogene requires expression of inducible phosphofructokinase/fructose-bisphosphatase 3 for cell growth and increased metabolic activity
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. © 2012 Macmillan Publishers Limited All rights reserved.
Keywords:	signal transduction; controlled study; unclassified drug; gene mutation; human cell; myeloproliferative disorder; janus kinase 2; nonhuman; flow cytometry; cell proliferation; animal cell; mouse; animals; mice; cell growth; animal experiment; animal model; rna interference; mice, scid; xenograft model antitumor assays; enzyme activity; cell line, tumor; protein tyrosine kinase; cell transformation, neoplastic; hypoxia; oncogene; cell strain hek293; messenger rna; cell transformation; reactive oxygen metabolite; glucose; real time polymerase chain reaction; bone marrow cell; point mutation; doxycycline; stat5 protein; stat5 transcription factor; cell metabolism; glucose transport; glycolysis; oxidative phosphorylation; short hairpin rna; complementary dna; glucose transporter type 1; lentivirinae; lactic acid; myeloid neoplasia; tyrosine kinase oncogene; glucose transporter; jak2; energy yield; pfkfb3; 6 phosphofructo 2 kinase; 6 phosphofructokinase; fructose 2,6 bisphosphatase 3; fructose-bisphosphatase; phosphofructokinase-2
Journal Title:	Leukemia
Volume:	26
Issue:	3
ISSN:	0887-6924
Publisher:	Nature Publishing Group
Date Published:	2012-03-01
Start Page:	481
End Page:	489
Language:	English
DOI:	10.1038/leu.2011.225
PROVIDER:	scopus
PMCID:	PMC3227767
PUBMED:	21860432
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-84857999965&partnerID=40&md5=8ca2a0f823b5e4d23df5b31da69d95c0
Notes:	--- - "Export Date: 2 April 2012" - "CODEN: LEUKE" - "Source: Scopus"

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