Chao Li1, Shuo Huang1, Jun Guo1, Cheng Wang2, Zhichao Huang3, Ruimin Huang4,5, Liang Liu6, Sheng Liang7, Hui Wang8. 1. Department of Nuclear Medicine, Xinhua Hospital, Shanghai Jiao Tong University, School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China. 2. Department of Nuclear Medicine, Renji Hospital, Shanghai Jiao Tong University, School of Medicine, 1630 Dongfang Road, Shanghai, 200127, China. 3. PINGSENG Healthcare, 999 Qujia Road, Kunshan, 215341, Jiangsu, China. 4. Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China. rmhuang@simm.ac.cn. 5. University of Chinese Academy of Sciences, No.19(A) Yuquan Road, Beijing, 100049, China. rmhuang@simm.ac.cn. 6. Department of Cardiology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai, 200233, China. 7. Department of Nuclear Medicine, Xinhua Hospital, Shanghai Jiao Tong University, School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China. liangsheng364214@163.com. 8. Department of Nuclear Medicine, Xinhua Hospital, Shanghai Jiao Tong University, School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China. wanghui@xinhuamed.com.cn.
Abstract
PURPOSE: This study aims to explore whether 4-(2S,4R)-[18F]fluoroglutamine (4-[18F]FGln) positron emission tomography (PET) imaging is helpful in identifying and monitoring MYCN-amplified neuroblastoma by enhanced glutamine metabolism. PROCEDURES: Cell uptake studies and dynamic small-animal PET studies of 4-[18F]FGln and 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) were conducted in human MYCN-amplified (IMR-32 and SK-N-BE (2) cells) and non-MYCN-amplified (SH-SY5Y cell) neuroblastoma cells and animal models. Subsequently, short hairpin RNA (shRNA) knockdown of alanine-serine-cysteine transporter 2 (ASCT2/SLC1A5) in IMR-32 cells and xenografts were investigated in vitro and in vivo. Western blot (WB), real-time polymerase chain reaction (RT-PCR), and immunofluorescence (IF) assays were used to measure the prevalence of ASCT2, Ki-67, and c-Caspase 3, respectively. RESULTS: IMR-32 and SK-N-BE (2) cells showed high glutamine uptake in vitro (31.6 ± 1.7 and 21.6 ± 6.6 %ID/100 μg). In the in vivo study, 4-[18F]FGln was localized in IMR-32, SK-N-BE (2), and SH-SY5Y tumors with a high uptake (6.6 ± 0.3, 5.6 ± 0.2, and 3.7 ± 0.1 %ID/g). The maximum uptake (tumor-to-muscle, T/M) of the IMR-32 and SK-N-BE (2) tumors (3.71 and 2.63) was significantly higher than that of SH-SY5Y (1.54) tumors (P < 0.001, P < 0.001). The maximum uptake of 4-[18F]FGln in IMR-32 and SK-N-BE (2) tumors was 2.3-fold and 2.1-fold higher than that of [18F]FDG, respectively. Furthermore, in the in vitro and in vivo studies, the maximum uptake of 4-[18F]FGln in shASCT2-IMR-32 cells and tumors was 2.1-fold and 2.5-fold lower than that of the shControl-IMR-32. No significant difference in [18F]FDG uptake was found between shASCT2-IMR-32 and shControl-IMR-32 cells and tumors. CONCLUSION: 4-[18F]FGln PET can provide a valuable clinical tool in the assessment of metabolic glutamine uptake in MYCN-amplified neuroblastoma. ASCT2-targeted therapy may provide a supplementary method in MYCN-amplified neuroblastoma treatment.
PURPOSE: This study aims to explore whether 4-(2S,4R)-[18F]fluoroglutamine (4-[18F]FGln) positron emission tomography (PET) imaging is helpful in identifying and monitoring MYCN-amplified neuroblastoma by enhanced glutamine metabolism. PROCEDURES: Cell uptake studies and dynamic small-animal PET studies of 4-[18F]FGln and 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) were conducted in humanMYCN-amplified (IMR-32 and SK-N-BE (2) cells) and non-MYCN-amplified (SH-SY5Y cell) neuroblastoma cells and animal models. Subsequently, short hairpin RNA (shRNA) knockdown of alanine-serine-cysteine transporter 2 (ASCT2/SLC1A5) in IMR-32 cells and xenografts were investigated in vitro and in vivo. Western blot (WB), real-time polymerase chain reaction (RT-PCR), and immunofluorescence (IF) assays were used to measure the prevalence of ASCT2, Ki-67, and c-Caspase 3, respectively. RESULTS: IMR-32 and SK-N-BE (2) cells showed high glutamine uptake in vitro (31.6 ± 1.7 and 21.6 ± 6.6 %ID/100 μg). In the in vivo study, 4-[18F]FGln was localized in IMR-32, SK-N-BE (2), and SH-SY5Y tumors with a high uptake (6.6 ± 0.3, 5.6 ± 0.2, and 3.7 ± 0.1 %ID/g). The maximum uptake (tumor-to-muscle, T/M) of the IMR-32 and SK-N-BE (2) tumors (3.71 and 2.63) was significantly higher than that of SH-SY5Y (1.54) tumors (P < 0.001, P < 0.001). The maximum uptake of 4-[18F]FGln in IMR-32 and SK-N-BE (2) tumors was 2.3-fold and 2.1-fold higher than that of [18F]FDG, respectively. Furthermore, in the in vitro and in vivo studies, the maximum uptake of 4-[18F]FGln in shASCT2-IMR-32 cells and tumors was 2.1-fold and 2.5-fold lower than that of the shControl-IMR-32. No significant difference in [18F]FDG uptake was found between shASCT2-IMR-32 and shControl-IMR-32 cells and tumors. CONCLUSION:4-[18F]FGln PET can provide a valuable clinical tool in the assessment of metabolic glutamine uptake in MYCN-amplified neuroblastoma. ASCT2-targeted therapy may provide a supplementary method in MYCN-amplified neuroblastoma treatment.
Entities:
Keywords:
ASCT2; Glutamine; MYCN; Neuroblastoma; PET
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