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      Reexamining cancer metabolism: lactate production for carcinogenesis could be the purpose and explanation of the Warburg Effect

      review-article
      1 , 2 , , 3
      Carcinogenesis
      Oxford University Press

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          Summary

          By reversing emphasis from precursor uptake to product accumulation and release, we posit that lactate production (‘lactagenesis’) supports carcinogenesis and it is the explanation and purpose of the Warburg effect. We posit that in carcinogenesis, aberrant cell signaling due to exaggerated and continually high lactate levels yields an inappropriate positive feedback loop that increases glucose uptake, glycolysis, lactate production and release, decreases mitochondrial function and clearance and upregulates glycolytic enzyme and monocarboxylate transporter expression thereby supporting angiogenesis, immune escape, cell migration, metastasis and self-sufficient metabolism, all of which encourage progression to cancer.

          Abstract

          Herein, we use lessons learned in exercise physiology and metabolism to propose that augmented lactate production (‘lactagenesis’), initiated by gene mutations, is the reason and purpose of the Warburg Effect and that dysregulated lactate metabolism and signaling are the key elements in carcinogenesis. Lactate-producing (‘lactagenic’) cancer cells are characterized by increased aerobic glycolysis and excessive lactate formation, a phenomenon described by Otto Warburg 93 years ago, which still remains unexplained. After a hiatus of several decades, interest in lactate as a player in cancer has been renewed. In normal physiology, lactate, the obligatory product of glycolysis, is an important metabolic fuel energy source, the most important gluconeogenic precursor, and a signaling molecule (i.e. a ‘lactormone’) with major regulatory properties. In lactagenic cancers, oncogenes and tumor suppressor mutations behave in a highly orchestrated manner, apparently with the purpose of increasing glucose utilization for lactagenesis purposes and lactate exchange between, within and among cells. Five main steps are identified (i) increased glucose uptake, (ii) increased glycolytic enzyme expression and activity, (iii) decreased mitochondrial function, (iv) increased lactate production, accumulation and release and (v) upregulation of monocarboxylate transporters MTC1 and MCT4 for lactate exchange. Lactate is probably the only metabolic compound involved and necessary in all main sequela for carcinogenesis, specifically: angiogenesis, immune escape, cell migration, metastasis and self-sufficient metabolism. We hypothesize that lactagenesis for carcinogenesis is the explanation and purpose of the Warburg Effect. Accordingly, therapies to limit lactate exchange and signaling within and among cancer cells should be priorities for discovery.

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          Most cited references189

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          On the origin of cancer cells.

          O WARBURG (1956)
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            Cancer genes and the pathways they control.

            The revolution in cancer research can be summed up in a single sentence: cancer is, in essence, a genetic disease. In the last decade, many important genes responsible for the genesis of various cancers have been discovered, their mutations precisely identified, and the pathways through which they act characterized. The purposes of this review are to highlight examples of progress in these areas, indicate where knowledge is scarce and point out fertile grounds for future investigation.
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              p53 regulates mitochondrial respiration.

              The energy that sustains cancer cells is derived preferentially from glycolysis. This metabolic change, the Warburg effect, was one of the first alterations in cancer cells recognized as conferring a survival advantage. Here, we show that p53, one of the most frequently mutated genes in cancers, modulates the balance between the utilization of respiratory and glycolytic pathways. We identify Synthesis of Cytochrome c Oxidase 2 (SCO2) as the downstream mediator of this effect in mice and human cancer cell lines. SCO2 is critical for regulating the cytochrome c oxidase (COX) complex, the major site of oxygen utilization in the eukaryotic cell. Disruption of the SCO2 gene in human cancer cells with wild-type p53 recapitulated the metabolic switch toward glycolysis that is exhibited by p53-deficient cells. That SCO2 couples p53 to mitochondrial respiration provides a possible explanation for the Warburg effect and offers new clues as to how p53 might affect aging and metabolism.
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                Author and article information

                Journal
                Carcinogenesis
                Carcinogenesis
                carcin
                Carcinogenesis
                Oxford University Press (UK )
                0143-3334
                1460-2180
                February 2017
                30 December 2016
                30 December 2016
                : 38
                : 2
                : 119-133
                Affiliations
                [1 ] Department of Physical Medicine and Rehabilitation, University of Colorado School of Medicine , Aurora, CO 80045, USA,
                [2 ] Physiology Laboratory, CU Sports Medicine and Performance Center , Boulder, CO 80309, USA and
                [3 ] Department of Integrative Biology, University of California , Berkeley, CA 94720, USA
                Author notes

                *To whom correspondence should be addressed. Tel: +1 303 315 9900; Fax: +1 303 315 9902; Email: inigo.sanmillan@ 123456ucdenver.edu

                Article
                bgw127
                10.1093/carcin/bgw127
                5862360
                27993896
                91f226ae-75db-4912-9fe9-340d06d5b3b5
                © The Author 2016. Published by Oxford University Press.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                History
                : 18 May 2016
                : 08 December 2016
                : 17 October 2016
                Page count
                Pages: 15
                Categories
                Review

                Oncology & Radiotherapy
                Oncology & Radiotherapy

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