期刊
CANCER RESEARCH
卷 75, 期 19, 页码 4109-4118出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-15-0857
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资金
- Cancer Research UK (CRUK) [C19212/A16628, C19212/A911376, 17242, 16465]
- National Institute for Health Research Cambridge Biomedical Research Centre
- School of Clinical Medicine at the University of Cambridge
- CRUK
- Engineering and Physical Sciences Research Council (EPSRC) Cancer Imaging Centre in Cambridge and Manchester
- European Union Seventh Framework Programme (FP7) under the Marie Curie Initial Training Network METAFLUX
- Calouste Gulbenkian Foundation
- Champalimaud Foundation
- Ministerio de Saude
- Fundacao para a Ciencia e Tecnologia, Portugal
- MRC [G1000265] Funding Source: UKRI
- Cancer Research UK [22310, 11359, 18974, 16465, 16466, 17242, 16628, 11562] Funding Source: researchfish
- Medical Research Council [G1000265] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0611-10163] Funding Source: researchfish
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 C-13 label between bicarbonate ((HCO3-)-C-13) and carbon dioxide ((CO2)-C-13), following injection of hyperpolarized (HCO3-)-C-13, using C-13-magnetic resonance spectroscopy (C-13-MRS) magnetization transfer measurements. P-31-MRS measurements of the chemical shift of the pH probe, 3-aminopropylphosphonate, and C-13-MRS measurements of the (HCO3-)-C-13/(CO2)-C-13 peak intensity ratio showed that CAIX overexpression lowered extracellular pH in these tumors. However, the C-13 measurements overestimated pH due to incomplete equilibration of the hyperpolarized C-13 label between the (HCO3-)-C-13 and (CO2)-C-13 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. (C) 2015 AACR.
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