Warburg Effects in Cancer and Normal Proliferating Cells: Two Tales of the Same Name

• Published in: Genomics, proteomics & bioinformatics Vol. 17; no. 3; pp. 273 - 286
• Main Authors: Sun, Huiyan, Chen, Liang, Cao, Sha, Liang, Yanchun, Xu, Ying
• Format: Journal Article
• Language: English
• Published: China Elsevier B.V 01.06.2019; Department of Biostatistics, School of Medicine, Indiana University, Indianapolis, IN 46202, USA%MOE Key Laboratory of Symbolic Computation and Knowledge Engineering, College of Computer Science and Technology,Jilin University, Changchun 130012, China; Computational Systems Biology Lab, Department of Biochemistry and Molecular Biology and Institute of Bioinformatics,University of Georgia, Athens, GA 30602, USA%Faculty of Health Sciences, University of Macau, Taipa, Macau SAR 999078, China%Computational Systems Biology Lab, Department of Biochemistry and Molecular Biology and Institute of Bioinformatics,University of Georgia, Athens, GA 30602, USA; Zhuhai Laboratory of MOE Key Laboratory of Symbolic Computation and Knowledge Engineering, Zhuhai College of Jilin University, Zhuhai 519041, China; The China-Japan Union Hospital, Jilin University, Changchun 130033, China; MOE Key Laboratory of Symbolic Computation and Knowledge Engineering, College of Computer Science and Technology,Jilin University, Changchun 130012, China; Elsevier; Oxford University Press
• Subjects: adenosine triphosphate; Adenosine Triphosphate - metabolism; Cancer; cell division; Cell Line, Tumor; Cell Proliferation; Cytosol - metabolism; Fenton reaction; Gene Expression Regulation; glycolysis; Glycolysis - genetics; Humans; Hydrogen Peroxide; Hydrogen-Ion Concentration; hydrolysis; intracellular space; Intracellular Space - metabolism; Iron; lactic acid; Membrane Transport Proteins - genetics; Membrane Transport Proteins - metabolism; neoplasm cells; neoplasms; Neoplasms - metabolism; Neoplasms - pathology; Original Research; pH homeostasis; Proteasome Endopeptidase Complex - metabolism; secretion; Time Factors; tissues; transcriptomics; transporters; Warburg effect; Cell proliferation; Fenton reaction; pH homeostasis; Cancer; Warburg effect
• DOI: 10.1016/j.gpb.2018.12.006
• ISSN: 1672-0229

It has been observed that both cancer tissue cells and normal proliferating cells (NPCs) have the Warburg effect. Our goal here is to demonstrate that they do this for different reasons. To accomplish this, we have analyzed the transcriptomic data of over 7000 cancer and control tissues of 14 cancer types in TCGA and data of five NPC types in GEO. Our analyses reveal that NPCs accumulate large quantities of ATPs produced by the respiration process before starting the Warburg effect, to raise the intracellular pH from ∼6.8 to ∼7.2 and to prepare for cell division energetically. Once cell cycle starts, the cells start to rely on glycolysis for ATP generation followed by ATP hydrolysis and lactic acid release, to maintain the elevated intracellular pH as needed by cell division since together the three processes are pH neutral. The cells go back to the normal respiration-based ATP production once the cell division phase ends. In comparison, cancer cells have reached their intracellular pH at ∼7.4 from top down as multiple acid-loading transporters are up-regulated and most acid-extruding ones except for lactic acid exporters are repressed. Cancer cells use continuous glycolysis for ATP production as way to acidify the intracellular space since the lactic acid secretion is decoupled from glycolysis-based ATP generation and is pH balanced by increased expressions of acid-loading transporters. Co-expression analyses suggest that lactic acid secretion is regulated by external, non-pH related signals. Overall, our data strongly suggest that the two cell types have the Warburg effect for very different reasons.