Pericellular p<scp>H</scp> homeostasis is a primary function of the <scp>W</scp>arburg effect: Inversion of metabolic systems to control lactate steady state in tumor cells

Mazzio, Elizabeth; Boukli, Nawal M.; Rivera, Nery; Soliman, Karam F.A.

doi:10.1111/j.1349-7006.2012.02206.x

Cited by 53 publications

(49 citation statements)

References 56 publications

(94 reference statements)

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“…Our data demonstrate that in the tumor models used in this study, LDH-A expression and pimonidazole binding (primarily dependent on low pO 2 ) (41) have similar but discordant spatial distributions, in good agreement with previous reports that lactic acidosis and hypoxia are not always interdependent (9,38,39). It is likely that tumor regions of poor vascularity and low pO 2 will also possess excess extracellular H + ions due to anaerobic glucose metabolism and local lactic acidosis.…”

Section: Discussionsupporting

confidence: 89%

Understanding the pharmacological properties of a metabolic PET tracer in prostate cancer

Viola-Villegas¹,

Carlin²,

Ackerstaff³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Generally, solid tumors (>400 mm 3 ) are inherently acidic, with more aggressive growth producing greater acidity. If the acidity could be targeted as a biomarker, it would provide a means to gauge the pace of tumor growth and degree of invasiveness, as well as providing a basis for predicting responses to pH-dependent chemotherapies. We have developed a 64 Cu pH (low) insertion peptide (pHLIP) for targeting, imaging, and quantifying acidic tumors by PET, and our findings reveal utility in assessing prostate tumors. The new pHLIP version limits indiscriminate healthy tissue binding, and we demonstrate its targeting of extracellular acidification in three different prostate cancer models, each with different vascularization and acid-extruding protein carbonic anhydrase IX (CAIX) expression. We then describe the tumor distribution of this radiotracer ex vivo, in association with blood perfusion and known biomarkers of acidity, such as hypoxia, lactate dehydrogenase A, and CAIX. We find that the probe reveals metabolic variations between and within tumors, and discriminates between necrotic and living tumor areas.

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Section: Discussionsupporting

confidence: 89%

Understanding the pharmacological properties of a metabolic PET tracer in prostate cancer

Viola-Villegas¹,

Carlin²,

Ackerstaff³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…The precise role of COX7A1 is not yet clear, however, two recent studies in mice reveal that a COX7A1 knockout gives rise to a cardiomyopathy phenotype with reduced Complex IV activity but increased ATP production [55] while a deletion of the heart-isoform of COX7A1 impairs muscle angiogenesis and OXPHOS [61]. Interestingly, COX7C has been shown to be phosphorylated and may play a signaling role [62] and in a separate study, the expression of COX7C was identified as one of several proteins regulated in the switch between glycolysis and OXPHOS in tumor cells [63]. In either case, it would appear that loss of one or both of these subunits from Complex IV would have a direct impact on the biochemistry of the MRC and could predispose the cells towards a metabolic situation that promotes tumor growth.…”

Section: Resultsmentioning

confidence: 98%

Structural Analysis of Mitochondrial Mutations Reveals a Role for Bigenomic Protein Interactions in Human Disease

Lloyd

McGeehan

2013

PLoS ONE

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Mitochondria are the energy producing organelles of the cell, and mutations within their genome can cause numerous and often severe human diseases. At the heart of every mitochondrion is a set of five large multi-protein machines collectively known as the mitochondrial respiratory chain (MRC). This cellular machinery is central to several processes important for maintaining homeostasis within cells, including the production of ATP. The MRC is unique due to the bigenomic origin of its interacting proteins, which are encoded in the nucleus and mitochondria. It is this, in combination with the sheer number of protein-protein interactions that occur both within and between the MRC complexes, which makes the prediction of function and pathological outcome from primary sequence mutation data extremely challenging. Here we demonstrate how 3D structural analysis can be employed to predict the functional importance of mutations in mtDNA protein-coding genes. We mined the MITOMAP database and, utilizing the latest structural data, classified mutation sites based on their location within the MRC complexes III and IV. Using this approach, four structural classes of mutation were identified, including one underexplored class that interferes with nuclear-mitochondrial protein interactions. We demonstrate that this class currently eludes existing predictive approaches that do not take into account the quaternary structural organization inherent within and between the MRC complexes. The systematic and detailed structural analysis of disease-associated mutations in the mitochondrial Complex III and IV genes significantly enhances the predictive power of existing approaches and our understanding of how such mutations contribute to various pathologies. Given the general lack of any successful therapeutic approaches for disorders of the MRC, these findings may inform the development of new diagnostic and prognostic biomarkers, as well as new drugs and targets for gene therapy.

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“…In addition to boosting tissue invasiveness, migratory potential [245,268] and altering drug sensitivity [269,270], an acidic culture condition can have profound effects on other aspects of cancer. Changes to metabolic patterns have been observed when cancer cells are cultured in acidic conditions, with a switch from reliance on aerobic glycolysis and production of lactic acid under a physiological pH to a reversion back to oxidative phosphorylation in an acidic environment [271]. Furthermore, culturing cancer cells in an acidic environment have also been demonstrated to increase autophagic flux [272] and reduce cell sensitivity to radiation therapy, potentially through prolonging the G2/M cell cycle arrest and allowing more time for repairing radiation-induced damage [273,274].…”

Section: Acidic Culture Conditionsmentioning

confidence: 99%

Lessons from patient-derived xenografts for better in vitro modeling of human cancer

Choi¹,

Lin²,

Gout³

et al. 2014

Advanced Drug Delivery Reviews

157

134

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The development of novel cancer therapeutics is often plagued by discrepancies between drug efficacies obtained in preclinical studies and outcomes of clinical trials. The inconsistencies can be attributed to a lack of clinical relevance of the cancer models used for drug testing. While commonly used in vitro culture systems are advantageous for addressing specific experimental questions, they are often gross, fidelity-lacking simplifications that largely ignore the heterogeneity of cancers as well as the complexity of the tumor microenvironment. Factors such as tumor architecture, interactions among cancer cells and between cancer and stromal cells, and an acidic tumor microenvironment are critical characteristics observed in patient-derived cancer xenograft models and in the clinic. By mimicking these crucial in vivo characteristics through use of 3D cultures, co-culture systems and acidic culture conditions, an in vitro cancer model/microenvironment that is more physiologically relevant may be engineered to produce results more readily applicable to the clinic.

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

Cited by 53 publications

References 56 publications

Understanding the pharmacological properties of a metabolic PET tracer in prostate cancer

Understanding the pharmacological properties of a metabolic PET tracer in prostate cancer

Structural Analysis of Mitochondrial Mutations Reveals a Role for Bigenomic Protein Interactions in Human Disease

Lessons from patient-derived xenografts for better in vitro modeling of human cancer

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