Pericellular pH homeostasis is a primary function of the Warburg effect: Inversion of metabolic systems to control lactate steady state in tumor cells

College of Pharmacy and Pharmaceutical Sciences, Florida A & M University, Tallahassee, Florida, USA.
Cancer Science (Impact Factor: 3.52). 03/2012; 103(3):422-32. DOI: 10.1111/j.1349-7006.2012.02206.x
Source: PubMed


The Warburg effect describes a heightened propensity of tumor cells to produce lactic acid in the presence or absence of O(2) . A generally held notion is that the Warburg effect is related to energy. Using whole-genome, proteomic MALDI-TOF-MS and metabolite analysis, we investigated the Warburg effect in malignant neuroblastoma N2a cells. The findings show that the Warburg effect serves a functional role in regulating acidic pericellular pH (pHe), which is mediated by metabolic inversion or a fluctuating dominance between glycolytic-rate substrate level phosphorylation (SLP) and mitochondrial (mt) oxidative phosphorylation (OXPHOS) to control lactic acid production. The results also show that an alkaline pHe caused an elevation in SLP/OXPHOS ratio (approximately 98% SLP/OXPHOS); while the ratio was approximately 56% at neutral pHe and approximately 93% in acidic pHe. Acidic pHe paralleled greater expression of mitochondrial biogenesis and OXPHOS genes, such as complex III-V (Uqcr10, Atp5 and Cox7c), mt Fmc1, Romo1, Tmem 173, Tomm6, aldehyde dehydrogenase, mt Sod2 mt biogenesis component PPAR-γ co-activator 1 adjunct to loss of mt fission (Mff). Moreover, acidic pHe corresponded to metabolic efficiency evidenced by a rise in mTOR nutrient sensor GβL, its downstream target (Eif4ebp1), insulin modulators (Trib3 and Fetub) and loss of catabolic (Hadhb, Bdh1 and Pygl)/glycolytic processes (aldolase C, pyruvate kinase, Nampt and aldose-reductase). In contrast, alkaline pHe initiated loss of mitofusin 2, complex II-IV (Sdhaf1, Uqcrq, Cox4i2 and Aldh1l2), aconitase, mitochondrial carrier triple repeat 1 and mt biosynthetic (Coq2, Coq5 and Coq9). In conclusion, the Warburg effect might serve as a negative feedback loop that regulates the pHe toward a broad acidic range by altering lactic acid production through inversion of metabolic systems. These effects were independent of changes in O(2) concentration or glucose supply.

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Available from: Karam F Soliman, Apr 18, 2014
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    • "Also, PDK2 increases accumulation of HIF-1 that may reflect the competing influences (Sun et al, 2009). The anticorrelation with the insulin modulator TRIB3, which is activated in hypoxic conditions and is associated with increased production of lactate and increased extracellular lactate levels, would also fit with this hypothesis (Mazzio et al, 2012). "
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    • "It has also been demonstrated that cancer-generated lactic acid and the resultant acidification of the micro-environment increase the expression of ARG1 in tumour-associated macrophages, characteristic of the M2 helper phenotype 31. Furthermore, another study showed that under physiological or slightly alkaline conditions, glycolysis was selectively up-regulated by neuroblastoma cells, whereas oxidative phosphorylation was preferred by the cells when the extracellular pH was acidic; these effects were independent of changes in oxygen concentration or glucose supply 32. Thus, aerobic glycolysis can serve as a negative feedback loop that adjusts the pericellular pH in tumours towards a broad acidic range by increased lactic acid production and secretion. "
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