title: M2 isoform of pyruvate kinase is dispensable for tumor maintenance and growth.
abstract: Many cancer cells have increased rates of aerobic glycolysis, a phenomenon termed the Warburg effect. In addition, in tumors there is a predominance of expression of the M2 isoform of pyruvate kinase (PKM2). M2 expression was previously shown to be necessary for aerobic glycolysis and to provide a growth advantage to tumors. We report that knockdown of pyruvate kinase in tumor cells leads to a decrease in the levels of pyruvate kinase activity and an increase in the pyruvate kinase substrate phosphoenolpyruvate. However, lactate production from glucose, although reduced, was not fully inhibited. Furthermore, we are unique in reporting increased serine and glycine biosynthesis from both glucose and glutamine following pyruvate kinase knockdown. Although pyruvate kinase knockdown results in modest impairment of proliferation in vitro, in vivo growth of established xenograft tumors is unaffected by PKM2 absence. Our findings indicate that PKM2 is dispensable for tumor maintenance and growth in vivo, suggesting that other metabolic pathways bypass its function.
authors.affiliation: Disease Area Oncology, Novartis Institutes for BioMedical Research, 4056 Basel, Switzerland. marta.cortes-cros@novartis.com
authors.forename: Marta
authors.initials: M
authors.lastname: Cortés-Cros
authors.forename: Christelle
authors.initials: C
authors.lastname: Hemmerlin
authors.forename: Stephane
authors.initials: S
authors.lastname: Ferretti
authors.forename: Juan
authors.initials: J
authors.lastname: Zhang
authors.forename: John S
authors.initials: JS
authors.lastname: Gounarides
authors.forename: Hong
authors.initials: H
authors.lastname: Yin
authors.forename: Alban
authors.initials: A
authors.lastname: Muller
authors.forename: Anne
authors.initials: A
authors.lastname: Haberkorn
authors.forename: Patrick
authors.initials: P
authors.lastname: Chene
authors.forename: William R
authors.initials: WR
authors.lastname: Sellers
authors.forename: Francesco
authors.initials: F
authors.lastname: Hofmann
mesh_terms: D002247:Carbon Isotopes / Q000378:metabolism; D045744:Cell Line, Tumor; D002852:Chromatography, Ion Exchange; D017931:DNA Primers / Q000235:genetics; D055785:Gene Knockdown Techniques; D006019:Glycolysis / Q000502:physiology*; D006801:Humans; D015151:Immunoblotting; D019344:Lactic Acid / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D009369:Neoplasms / Q000503:physiopathology*; D010728:Phosphoenolpyruvate / Q000378:metabolism; D011770:Pyruvate Kinase / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053719:Tandem Mass Spectrometry
chemical_list: D002247:Carbon Isotopes; D017931:DNA Primers; D019344:Lactic Acid; D010728:Phosphoenolpyruvate; D011770:Pyruvate Kinase