The role of LAT1 in 18 F-DOPA uptake in malignant gliomas
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LABORATORY INVESTIGATION
The role of LAT1 in
18
F-DOPA uptake in malignant gliomas
Ryan S. Youland • Gaspar J. Kitange • Timothy E. Peterson • Deanna H. Pafundi Judi A. Ramiscal • Jenny L. Pokorny • Caterina Giannini • Nadia N. Laack • Ian F. Parney • Val J. Lowe • Debra H. Brinkmann • Jann N. Sarkaria
•
Received: 25 July 2012 / Accepted: 10 October 2012 / Published online: 20 October 2012 Ó Springer Science+Business Media New York 2012
Abstract Positron emission tomography (PET) imaging with the amino acid tracer 6-18F-fluoro-L-3,4-dihydroxyphenylalanine (18F-DOPA) may provide better spatial and functional information in human gliomas than CT or MRI alone. The L-type amino acid transporter 1 (LAT1) is responsible for membrane transport of large neutral amino acids in normal cells. This study assessed the relationship between LAT1 expression and 18F-DOPA uptake in human astrocytomas. Endogenous LAT1 expression was measured in established glioblastoma (GBM) cell lines and primary GBM xenografts using Western blotting and quantitative reverse transcription polymerase chain reaction (qRT-PCR). Uptake of 18F-DOPA was approximated in vitro using 3H-L-DOPA as an analog. Uptake of 3H-L-DOPA was assessed in cells expressing LAT1 shRNA or LAT1 siRNA
R. S. Youland J. A. Ramiscal College of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA e-mail: [email protected] G. J. Kitange D. H. Pafundi J. L. Pokorny N. N. Laack D. H. Brinkmann J. N. Sarkaria (&) Department of Radiation Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA e-mail: [email protected] T. E. Peterson I. F. Parney Department of Neurosurgery, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA C. Giannini Department of Pathology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA V. J. Lowe Department of Radiology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
and compared to non-targeted (NT) control shRNA or siRNA sequences, respectively. To demonstrate the clinical relevance of these findings, LAT1 immunofluorescence staining was compared with corresponding regions of 18 F-DOPA PET uptake in patients with newly diagnosed astrocytomas. LAT1 mRNA and protein expression varies in GBM, and the extent of 3H-L-DOPA uptake was positively correlated with endogenous LAT1 expression. Stable shRNA-mediated LAT1 knockdown in T98 and GBM28 reduced 3H-L-DOPA uptake relative to NT shRNA by 57 (P \ 0.0001) and 52 % (P \ 0.001), respectively. Transient siRNA-mediated LAT1 knockdown in T98 reduced 3 H-L-DOPA uptake relative to NT siRNA up to 68 % (P \ 0.01). In clinical samples, LAT1 expression positively correlated with 18F-DOPA PET uptake (P = 0.04). Expression of LAT1 is strongly associated with 3 H-L-DOPA uptake in vitro and 18F-DOPA uptake in patient biopsy samples. These results define LAT1 as a key determinant of 18F-DOPA accumulation in GBM. Keywords 18F-DOPA PET/CT Glioma Glioblastoma Amino acid transport
Introduction Positron emission tomography (PET)-CT allows a fun
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