Warburg and Crabtree Effects in Premalignant Barrett's Esophagus Cell Lines with Active Mitochondria

Martin T Suchorolski,Brian J Reid,David Hockenbery,Carissa A Sanchez,Thomas G Paulson,Yidong Bai

doi:10.1371/journal.pone.0056884

Martin T Suchorolski, Brian J Reid + Show 4 more

Open Access

https://doi.org/10.1371/journal.pone.0056884

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Journal: PloS one	Publication Date: Feb 27, 2013
Citations: 36	License type: CC BY 4.0

Affiliation: University of Washington, Fred Hutch Cancer Center

Abstract

BackgroundIncreased glycolysis is a hallmark of cancer metabolism, yet relatively little is known about this phenotype at premalignant stages of progression. Periodic ischemia occurs in the premalignant condition Barrett's esophagus (BE) due to tissue damage from chronic acid-bile reflux and may select for early adaptations to hypoxia, including upregulation of glycolysis.Methodology/Principal FindingsWe compared rates of glycolysis and oxidative phosphorylation in four cell lines derived from patients with BE (CP-A, CP-B, CP-C and CP-D) in response to metabolic inhibitors and changes in glucose concentration. We report that cell lines derived from patients with more advanced genetically unstable BE have up to two-fold higher glycolysis compared to a cell line derived from a patient with early genetically stable BE; however, all cell lines preserve active mitochondria. In response to the glycolytic inhibitor 2-deoxyglucose, the most glycolytic cell lines (CP-C and CP-D) had the greatest suppression of extra-cellular acidification, but were able to compensate with upregulation of oxidative phosphorylation. In addition, these cell lines showed the lowest compensatory increases in glycolysis in response to mitochondrial uncoupling by 2,4-dinitrophenol. Finally, these cell lines also upregulated their oxidative phosphorylation in response to glucose via the Crabtree effect, and demonstrate a greater range of modulation of oxygen consumption.Conclusions/SignificanceOur findings suggest that cells from premalignant Barrett's esophagus tissue may adapt to an ever-changing selective microenvironment through changes in energy metabolic pathways typically associated with cancer cells.

Highlights

Two well-known differences in energy metabolism have been shown to exist between normal and cancer cells: the Warburg and Crabtree effects
To determine if late-stage Barrett’s esophagus (BE) cell lines demonstrate increased glycolysis and/or decreased oxidative phosphorylation compared to an early-stage BE cell line, extracellular acidification rates (ECAR) and oxygen consumption rates (OCR) were measured using the Seahorse XF24 analyzer in an early-stage BE cell line (CP-A), three late-stage BE cell lines (CP-B, -C, and -D), and a fibroblast control cell line (CRL-4001)
This study provides the first evidence that cell lines derived from later-stages of the premalignant condition Barrett’s esophagus have increased glycolysis compared to early-stage BE, while preserving mitochondrial function

Summary

Introduction

Two well-known differences in energy metabolism have been shown to exist between normal and cancer cells: the Warburg and Crabtree effects. Warburg reported reduced oxygen consumption in several cancers and postulated that damaged mitochondria were the cause of increased glycolysis [2]. Cancer cells have been shown to be different from normal cells by reversibly down-regulating their oxygen consumption in response to increases in glucose: the Crabtree effect [8]. Both of these metabolic effects are thought to be protective and contribute to cancer cell survival in a dynamic environment periodically experiencing hypoxia [9]. Periodic ischemia occurs in the premalignant condition Barrett’s esophagus (BE) due to tissue damage from chronic acid-bile reflux and may select for early adaptations to hypoxia, including upregulation of glycolysis

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