Carbonic Anhydrase Activity Monitored In Vivo by Hyperpolarized 13C-Magnetic Resonance Spectroscopy Demonstrates Its Importance for pH Regulation in Tumors

Ferdia A. Gallagher, Helen Sladen, Mikko I. Kettunen, Eva M. Serrao, Tiago B. Rodrigues, Alan Wright, Andrew B. Gill, Sarah McGuire, Thomas C. Booth, Joan Boren, Alan McIntyre, Jodi L. Miller, Shen-Han Lee, Davina Honess, Sam E. Day, De-En Hu, William J. Howat, Adrian L. Harris, Kevin M. Brindle

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38 Citations (Scopus)

Abstract

Carbonic anhydrase buffers tissue pH by catalyzing the rapid interconversion of carbon dioxide (CO2) and bicarbonate (HCO3-). We assessed the functional activity of CAIX in two colorectal tumor models, expressing different levels of the enzyme, by measuring the rate of exchange of hyperpolarized 13C label between bicarbonate (H13CO3-) and carbon dioxide (13CO2), following injection of hyperpolarized H13CO3-, using 13C-magnetic resonance spectroscopy (13C-MRS) magnetization transfer measurements. 31P-MRS measurements of the chemical shift of the pH probe, 3-aminopropylphosphonate, and 13C-MRS measurements of the H13CO3-/13CO2 peak intensity ratio showed that CAIX overexpression lowered extracellular pH in these tumors. However, the 13C measurements overestimated pH due to incomplete equilibration of the hyperpolarized 13C label between the H13CO3- and 13CO2 pools. Paradoxically, tumors overexpressing CAIX showed lower enzyme activity using magnetization transfer measurements, which can be explained by the more acidic extracellular pH in these tumors and the decreased activity of the enzyme at low pH. This explanation was confirmed by administration of bicarbonate in the drinking water, which elevated tumor extracellular pH and restored enzyme activity to control levels. These results suggest that CAIX expression is increased in hypoxia to compensate for the decrease in its activity produced by a low extracellular pH and supports the hypothesis that a major function of CAIX is to lower the extracellular pH. Cancer Res; 75(19); 4109textendash18. textcopyright2015 AACR.
Original languageEnglish
Pages (from-to)4109-4118
Number of pages10
JournalCancer Research
Volume75
Issue number19
Early online date6 Aug 2015
DOIs
Publication statusPublished - Oct 2015

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