| Pericellular pH homeostasis is a primary function of the Warburg effect; Inversion of metabolic systems to control lactate steady state in tumor cells. | |
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MedLine Citation:
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PMID: 22320183 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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The Warburg effect describes a heightened propensity of tumor cells to produce lactic acid in the presence or absence of O(2) . Currently, a generally held notion is that the Warburg effect is related to energy. Using whole-genome, proteomic MALDI-TOF-MS and metabolite analysis, we investigate the Warburg effect in malignant 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. Alkaline pHe elevated SLP/OXPHOS ratio (῀98% SLP/OXPHOS); vs. neutral (῀56% SLP/OXPHOS) or acidic (῀93% OXPHOS/SLP). 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 adjunct to loss of mt fission (Mff) and mt biogenesis component PPAR-γ co-activator 1. Moreover, acidic pHe corresponded to metabolic efficiency evidenced by a rise in mTOR nutrient sensor GßL, its downstream target (Eif4ebp1), insulin modulators (Trib3,Fetub) and loss of catabolic (Hadhb,Bdh1,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,Aldh1l2), aconitase, mitochondrial carrier triple repeat 1 and mt biosynthetic (Coq2,Coq5,Coq9). In conclusion, the Warburg effect may serve as negative feed-back loop which regulates the pHe toward a broad acidic range by altering lactic acid production through inversion of metabolic systems. These effects were independent of change in O(2) concentration or glucose supply. © 2012 Japanese Cancer Association. |
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Authors:
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Elizabeth A Mazzio; Nawal Boukli; Nery Rivera; Karam F A Soliman |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-2-9 |
Journal Detail:
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Title: Cancer science Volume: - ISSN: 1349-7006 ISO Abbreviation: - Publication Date: 2012 Feb |
Date Detail:
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Created Date: 2012-2-10 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101168776 Medline TA: Cancer Sci Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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© 2012 Japanese Cancer Association. |
Affiliation:
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College of Pharmacy and Pharmaceutical Sciences, Florida A & M University, Tallahassee, Florida, 32307, USA. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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