Ras transformation requires metabolic control by 6-phosphofructo-2-kinase

S. Telang, A. Yalcin, A. L. Clem, R. Bucala, A. N. Lane, J. W. Eaton, J. Chesney

Research output: Contribution to journalArticlepeer-review

143 Scopus citations


Neoplastic cells transport large amounts of glucose in order to produce anabolic precursors and energy within the inhospitable environment of a tumor. The ras signaling pathway is activated in several cancers and has been found to stimulate glycolytic flux to lactate. Glycolysis is regulated by ras via the activity of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases (PFK2/FBPase), which modulate the intracellular concentration of the allosteric glycolytic activator, fructose-2,6-bisphosphate (F2,6BP). We report herein that sequential immortalization and ras-transformation of mouse fibroblasts or human bronchial epithelial cells paradoxically decreases the intracellular concentration of F2,6BP. This marked reduction in the intracellular concentration of F2,6BP sensitizes transformed cells to the antimetabolic effects of PFK2/FBPase inhibition. Moreover, despite co-expression of all four mRNA species (PFKFB1-4), heterozygotic genomic deletion of the inducible PFKFB3 gene in ras-transformed mouse lung fibroblasts suppresses F2,6BP production, glycolytic flux to lactate, and growth as soft agar colonies or tumors in athymic mice. These data indicate that the PFKFB3 protein product may serve as an essential downstream metabolic mediator of oncogenic ras, and we propose that pharmacologic inhibition of this enzyme should selectively suppress the high rate of glycolysis and growth by cancer cells.

Original languageEnglish
Pages (from-to)7225-7234
Number of pages10
Issue number55
StatePublished - Nov 23 2006

Bibliographical note

Funding Information:
We thank Robert Mitchell for providing the rasV12 and LT retroviruses and Barrett Rollins for providing the hT, hT/Lt and hT/LT/ras bronchial epithelial cells. We gratefully acknowledge helpful discussions with Douglas Dean and Otto Grubraw. This work was supported by the following grants: NIH 1P20 RR18733 (JC), NIH 1 R01 CA11642801 (JC), and the P Morris External Research Program (JC and JWE).


  • Metabolism
  • Phosphofructokinase
  • ras

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research


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