Open AccessPericellular p H homeostasis is a primary function of the W arburg effect: Inversion of metabolic systems to control lactate steady state in tumor cells
Author(s) -
Mazzio Elizabeth A.,
Boukli Nawal,
Rivera Nery,
Soliman Karam F. A.
Publication year - 2012
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2012.02206.x
Subject(s) - warburg effect , glycolysis , tfam , oxidative phosphorylation , mitochondrial biogenesis , chemistry , biochemistry , lactic acid , anaerobic glycolysis , biology , mitochondrion , metabolism , bacteria , genetics
The W arburg 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 W arburg effect is related to energy. Using whole‐genome, proteomic MALDI ‐ TOF ‐ MS and metabolite analysis, we investigated the W arburg effect in malignant neuroblastoma N 2a cells. The findings show that the W arburg effect serves a functional role in regulating acidic pericellular p H (p H e), 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 p H e paralleled greater expression of mitochondrial biogenesis and OXPHOS genes, such as complex III–V ( U qcr10, A tp5 and C ox7c), mt F mc1, R omo1, T mem 173, T omm6, aldehyde dehydrogenase, mt S od2 mt biogenesis component PPAR‐γ co‐activator 1 adjunct to loss of mt fission ( Mff ). Moreover, acidic p H e corresponded to metabolic efficiency evidenced by a rise in m TOR nutrient sensor GβL , its downstream target ( E if4ebp1), insulin modulators ( T rib3 and F etub) and loss of catabolic ( H adhb, B dh1 and P ygl)/glycolytic processes (aldolase C , pyruvate kinase, N ampt and aldose‐reductase). In contrast, alkaline p H e initiated loss of mitofusin 2, complex II–IV ( S dhaf1, U qcrq, C ox4i2 and A ldh1l2), aconitase, mitochondrial carrier triple repeat 1 and mt biosynthetic ( C oq2, C oq5 and C oq9). In conclusion, the W arburg effect might serve as a negative feedback loop that regulates the p H e 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. ( Cancer Sci , 2012; 103: 422–432)