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Fluorocholine transport mediated by the organic cation transporter 2 (OCT2,SLC22A2): implication for imaging of kidney tumors


Visentin, Michele; Torozi, Angelo; Gai, Zhibo; Hausler, Stephanie; Li, Chao; Hiller, Christian; Schraml, Peter H; Moch, Holger; Kullak-Ublick, Gerd A (2018). Fluorocholine transport mediated by the organic cation transporter 2 (OCT2,SLC22A2): implication for imaging of kidney tumors. Drug Metabolism and Disposition, 46(8):1129-1136.

Abstract

[18F]fluorocholine is the fluorinated analogue of [11C]choline and is used in positron emission tomography (PET) to monitor tumor metabolic activity. While important to optimize its use and expand the clinical indications, the molecular determinants of fluorocholine cellular uptake are poorly characterized. Here, we described the influx kinetics of fluorocholine mediated by the organic cation transporter 2 (OCT2, SLC22A2) and compared with that of choline. Then, we characterized the expression pattern of OCT2 in renal cell carcinoma (RCC). In HEK293 cells stably transfected with OCT2 fluorocholine influx kinetics was biphasic suggesting two independent binding sites: a high-affinity (Km = 14±8 μ;M, Vmax=1.3±0.5 nmol mg-1 min-1) and a low affinity component (Km = 1.8 ± 0.3 mM, Vmax=104±4.5 nmol mg-1 min-1). Notably, choline was found to be transported with sigmoidal kinetics typical of homotropic positive cooperativity (h=1.2, 95% CI 1.1-1.3). OCT2 mRNA expression level was found significantly decreased in primary but not in metastatic RCC. Tissue microarray immunostaining of 216 RCC biopsies confirmed that protein expression was consistent with the mRNA data. The kinetic properties described here suggest that OCT2 is likely to play a dominant role in [18F]fluorocholine uptake in vivo. OCT2 altered expression in primary and metastatic cancer cells, as compared with the surrounding tissues, could be exploited in RCC imaging, especially to increase the detection sensitivity for small metastatic lesions, a major clinical challenge during the initial staging of RCC.

Abstract

[18F]fluorocholine is the fluorinated analogue of [11C]choline and is used in positron emission tomography (PET) to monitor tumor metabolic activity. While important to optimize its use and expand the clinical indications, the molecular determinants of fluorocholine cellular uptake are poorly characterized. Here, we described the influx kinetics of fluorocholine mediated by the organic cation transporter 2 (OCT2, SLC22A2) and compared with that of choline. Then, we characterized the expression pattern of OCT2 in renal cell carcinoma (RCC). In HEK293 cells stably transfected with OCT2 fluorocholine influx kinetics was biphasic suggesting two independent binding sites: a high-affinity (Km = 14±8 μ;M, Vmax=1.3±0.5 nmol mg-1 min-1) and a low affinity component (Km = 1.8 ± 0.3 mM, Vmax=104±4.5 nmol mg-1 min-1). Notably, choline was found to be transported with sigmoidal kinetics typical of homotropic positive cooperativity (h=1.2, 95% CI 1.1-1.3). OCT2 mRNA expression level was found significantly decreased in primary but not in metastatic RCC. Tissue microarray immunostaining of 216 RCC biopsies confirmed that protein expression was consistent with the mRNA data. The kinetic properties described here suggest that OCT2 is likely to play a dominant role in [18F]fluorocholine uptake in vivo. OCT2 altered expression in primary and metastatic cancer cells, as compared with the surrounding tissues, could be exploited in RCC imaging, especially to increase the detection sensitivity for small metastatic lesions, a major clinical challenge during the initial staging of RCC.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Pathology and Molecular Pathology
04 Faculty of Medicine > University Hospital Zurich > Clinic for Clinical Pharmacology and Toxicology
Dewey Decimal Classification:610 Medicine & health
Uncontrolled Keywords:Pharmacology, Pharmaceutical Science
Language:English
Date:2018
Deposited On:12 Jun 2018 14:20
Last Modified:04 Sep 2018 13:00
Publisher:American Society for Pharmacology and Experimental Therapeutics
ISSN:0090-9556
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1124/dmd.118.081091
PubMed ID:29794161

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