Control of glycolytic flux by AMP-activated protein kinase in tumor cells adapted to low ph1

Erin E. Mendoza, Michael G. Pocceschi, Xiangul Kong, Dennis B. Leeper, Jaime Caro, Kirsten Limesand, Randy M Burd

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Tumor cells grow in nutrient- and oxygen-deprived microenvironments and adapt to the suboptimal growth conditions by altering their metabolic pathways. This adaptation process commonly results in a tumor phenotype that displays a high rate of aerobic glycolysis and aggressive tumor characteristics. The glucose regulatory molecule, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), is a bifunctional enzyme that is central to glycolytic flux and is downstream of the metabolic stress sensor AMP-activated protein kinase (AMPK), which has been suggested to modulate glycolysis and possibly activate isoforms of PFKFB, specifically PFKFB3 expressed in tumor cells. Our results demonstrated that long-term low pH exposure induced AMPK activation, which resulted in the up-regulation of PFKFB3 and an increase in its serine residue phosphorylation. Pharmacologic activation of AMPK resulted in an increase in PFKFB3 as well as an increase in glucose consumption, whereas in contrast, inhibition of AMPK resulted in the down-regulation of PFKFB3 and decreased glycolysis. PFKFB3 overexpression in DB-1 tumor cells induced a high rate of glycolysis and inhibited oxygen consumption, confirming its role in controlling glycolytic flux. These results show that low pH is a physiological stress that can promote a glycolytic phenotype commonly associated with tumorigenesis. The implications are that the tumor microenviroment contributes to tumor growth and treatment resistance.

Original languageEnglish (US)
Pages (from-to)208-216
Number of pages9
JournalTranslational Oncology
Volume5
Issue number3
DOIs
StatePublished - Jun 2012

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AMP-Activated Protein Kinases
Fructose
Glycolysis
Phosphotransferases
Neoplasms
Physiological Stress
Phosphofructokinase-2
Phenotype
Glucose
Growth
Metabolic Networks and Pathways
Oxygen Consumption
Serine
Protein Isoforms
Carcinogenesis
Up-Regulation
Down-Regulation
Phosphorylation
Oxygen
Food

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Control of glycolytic flux by AMP-activated protein kinase in tumor cells adapted to low ph1. / Mendoza, Erin E.; Pocceschi, Michael G.; Kong, Xiangul; Leeper, Dennis B.; Caro, Jaime; Limesand, Kirsten; Burd, Randy M.

In: Translational Oncology, Vol. 5, No. 3, 06.2012, p. 208-216.

Research output: Contribution to journalArticle

Mendoza, Erin E. ; Pocceschi, Michael G. ; Kong, Xiangul ; Leeper, Dennis B. ; Caro, Jaime ; Limesand, Kirsten ; Burd, Randy M. / Control of glycolytic flux by AMP-activated protein kinase in tumor cells adapted to low ph1. In: Translational Oncology. 2012 ; Vol. 5, No. 3. pp. 208-216.
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