Abstract 34: Oncogenic tyrosine kinases phosphorylate and inhibit PKM2 to provide a metabolic advantage to tumor growth
Authors: Taro Hitosugi, Sumin Kang, Matthew G. Vander Heiden, Tae-Wook Chung, Sagar Lonial, Xu Wang, Georgia Z. Chen, Jianxin Xie, Ting-Lei Gu, Roberto D. Polakiewicz, Johannes L. Roesel, Titus Boggon, Fadlo Khuri, D. Gary Gilliland, Lewis C. Cantley, Jonathan Kaufman, Jing Chen
Journal: Cancer Research (2010)

Abstract Cancer cells show increased aerobic glycolysis and enhanced lactate production compared to healthy cells, a phenomenon known as the Warburg effect. Cell surface growth factor receptors, which often carry tyrosine kinase activities in their cytoplasmic domains, are overexpressed in many human cancers and are believed to play a key role in determining cell metabolism. Thus, we explored the hypothesis that tyrosine kinase signaling, which is commonly increased in tumors, regulates the Warburg effect and contributes to tumorigenesis and maintenance of the tumor. We performed phospho-proteomics studies and found that oncogenic forms of fibroblast growth factor (FGF) receptor type 1 (FGFR1) inhibit the pyruvate kinase M2 isoform (PKM2) in cancer cells. Pyruvate kinase is a rate-limiting enzyme during glycolysis and catalyzes the production of pyruvate and ATP from phosphoenolpyruvate (PEP) and ADP. Recent studies demonstrated that the enzymatic activity of the pyruvate kinase M2 isoform (PKM2) is inhibited by phosphotyrosine binding; moreover, these researchers found that PKM2 is crucial for aerobic glycolysis and provides a growth advantage to tumors. However, it remains unclear which tyrosine kinase pathways are physiologically responsible for this inhibition of PKM2 activity and which protein factors undergo tyrosine phosphorylation, allowing them to bind to and thereby inhibit PKM2. We found that PKM2 is itself tyrosine phosphorylated in cancer cells and such a physiological modification of PKM2 promotes the switch to aerobic glycolysis from oxidative phosphorylation. FGFR1 directly phosphorylates PKM2 at tyrosine residue 105 (Y105). This inhibits the formation of active, tetrameric PKM2 by disrupting binding of the PKM2 cofactor fructose-1,6-bisphosphate (FBP). Moreover, we found that phosphorylation of PKM2 Y105 is common in human cancers. Immunoblotting revealed that PKM2 is phosphorylated at Y105 in diverse human breast cancer, lung cancer, prostate cancer and leukemia cell lines. Oncogenic tyrosien kianses including BCR-ABL, FLT3-ITD and JAK2 also directly phosphorylate PKM2 Y105 in in vitro kinase assays using purified proteins. Furthermore, the presence of a PKM2 mutant in which phenylalanine is substituted for Y105 (Y105F) in cancer cells leads to decreased cell proliferation under hypoxic conditions, increased oxidative phosphorylation with reduced lactate production, and reduced tumor growth in xenografts in nude mice. Our findings suggest that tyrosine phosphorylation regulates PKM2 to provide a metabolic advantage to tumor cells, thereby promoting tumor growth. This may represent a common, short-term molecular mechanism underlying the Warburg effect in both leukemias and solid tumors, in addition to the chronic changes believed to be regulated by transcription factors, including hypoxia inducible factor 1 and Myc. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 34.