The neutral amino acid transporter ASCT2 is overexpressed in human colorectal adenomas and carcinomas

Witte, Deborah; Carlson, Nicole; Ali, Najeeba; Younes, Mamoun

doi:10.1016/s0016-5085(00)83228-x

Cited by 37 publications

(52 citation statements)

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“…These amino acid transporters have important roles in anti-18 F-FACBC transport. Furthermore, it has been reported that ASCT2 expression is associated with aggressive biologic behavior in colorectal adenocarcinomas (29). Witte et al (29) showed that the survival of colorectal adenocarcinoma patients decreases with an increased percentage of ASCT2-positive cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Putative Transport Mechanism and Intracellular Fate of Trans-1-Amino-3-¹⁸F-Fluorocyclobutanecarboxylic Acid in Human Prostate Cancer

Okudaira¹,

Shikano²,

Nishii³

et al. 2011

J Nucl Med

124

110

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Trans-1-amino-3-18 F-fluorocyclobutanecarboxylic acid (anti-18 F-FACBC) is an amino acid PET tracer that has shown promise for visualizing prostate cancer. Therefore, we aimed to clarify the anti-18 F-FACBC transport mechanism in prostate cancer cells. We also studied the fate of anti-18 F-FACBC after it is transported into cells. Methods: For convenience, because of their longer half-lives, 14 C compounds were used instead of 18 F-labeled tracers. Trans-1-amino-3-fluoro-1-14 C-cyclobutanecarboxylic acid ( 14 C-FACBC) uptake was examined in human prostate cancer DU145 cells with the following substrates of amino acid transporters: a-(methylamino) isobutyric acid (a system A-specific substrate) and 2-amino-2-norbornanecarboxylic acid (a system L-specific substrate). The messenger RNA expression of amino acid transporters in human prostate cancer specimens was analyzed by complementary DNA microarray and quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). Gene expression in DU145 cells was analyzed by qRT-PCR. We also examined the knockdown effect of the amino acid transporters system ASC transporter 2 (ASCT2) and sodium-coupled neutral amino acid transporter 2 (SNAT2) on 14 C-FACBC uptake. In addition, the possibility of 14 C-FACBC incorporation into proteins was examined. Results: 14 C-FACBC uptake by DU145 cells was markedly decreased to approximately 20% in the absence of Na 1 , compared with that in its presence, indicating that Na 1 -dependent transporters are mainly responsible for the uptake of this tracer. Moreover, 2-amino-2-norbornanecarboxylic acid inhibited the transport of 14 C-FACBC to the basal level in Na 1 -free buffer. In contrast, a-(methylamino) isobutyric acid did not inhibit 14 C-FACBC accumulation in DU145 cells. Human prostate tumor specimens and DU145 cells had similar messenger RNA expression patterns of amino acid transporter genes. Although SNAT2 and ASCT2 are 2 major amino acid transporters expressed in prostate tumor tissues and DU145 cells, ASCT2 knockdown using small interfering RNA was more effective in lowering 14 C-FACBC transport than SNAT2. Almost all intracellular 14 C-FACBC was recovered from the nonprotein fraction. Conclusion: ASCT2, which is a Na 1 -dependent amino acid transporter, and to a lesser extent Na 1 -independent transporters play a role in the uptake of 14 C-FACBC by DU145 cells. Among the Na 1 -independent transporters, system L transporters are also involved in the transport of 14 C-FACBC. Moreover, 14 C-FACBC is not incorporated into proteins in cells. These findings suggest a possible mechanism of anti-18 F-FACBC PET for prostate cancer.

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Section: Discussionmentioning

confidence: 99%

Putative Transport Mechanism and Intracellular Fate of Trans-1-Amino-3-¹⁸F-Fluorocyclobutanecarboxylic Acid in Human Prostate Cancer

Okudaira¹,

Shikano²,

Nishii³

et al. 2011

J Nucl Med

124

110

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“…Indeed, it has been shown that the expression of GLUT1, a transporter for glucose, is promoted in cancer cells (3,4). Expression of glutamine transporters such as ASCT2 is also facilitated (5,6), and this would support the cellular abundance of glutamine, which is consumed as a source of nitrogen and energy in tumor cells (7). The coordination of expression of highly efficient transporters for organic materials is requisite for powerful consumption of resources to ensure sustained cancer cell proliferation (8), and disruption of this system would lead to failure of tumor growth.…”

Section: Introductionmentioning

confidence: 99%

c-Myc is crucial for the expression of LAT1 in MIA Paca-2 human pancreatic cancer cells

Hayashi

Jutabha

Endou³

et al. 2012

Oncology Reports

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Abstract. Tumor cells take up a massive amount of nutrition compared to normal cells for increased metabolism. Therefore, special transporters for organic materials are required to satisfy the powerful consumption of nutrition in tumor cells. L-type amino acid transporter 1 (LAT1) incorporates large neutral amino acids, most of which are also categorized as essential amino acids, into cells in a Na + -independent manner. Because of its high expression levels in a variety of cancer cells, it is speculated that LAT1 functions as a key transporter for highly effective delivery of essential amino acids into cancer cells. In this regard, LAT1 inhibitor is expected to have clinical benefit for cancer therapy. However, the molecular mechanism of enrichment of LAT1 in cancer cells remains poorly understood. Here, we show that a proto-oncogene, c-Myc, is a critical positive regulator of LAT1 expression in MIA Paca-2 human pancreatic cancer cells. The uptake of leucine, a representative neutral amino acid, was strictly dependent on LAT1 in MIA Paca-2 cells, and siRNA-mediated knockdown of LAT1 inhibited cell proliferation. Diminished c-Myc expression with siRNA resulted in severe reduction of LAT1 protein levels as well as mRNA levels, which, in turn, led to a significant defect of leucine incorporation. The LAT1 promoter has a canonical c-Myc binding sequence and overexpression of c-Myc increased LAT1 promoter activity, whereas mutation of c-Myc binding site diminished this effect. Our results suggest biological significance of LAT1 in tumor growth and molecular machinery that could explain why LAT1 is preferentially expressed in cancer cells.

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“…An increased expression of ASCT2 has also been documented in several types of primary tumors [14,23]. Experimental evidence has shown that the ASCT2 gene is expressed in and mediates most of the glutamine uptake in human hepatoma, breast carcinoma, neuroblastoma, colon carcinoma, and C6 glioma cell lines [1,2,4,5,11,12,17,20,21].…”

mentioning

confidence: 99%

cDNA Sequence and Tissue Distribution of Canine Na-Dependent Neutral Amino Acid Transporter 2 (ASCT 2)

Ochiai

Onda

Ogihara

et al. 2012

The Journal of Veterinary Medical Science

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ABSTRACT. A full-length cDNA sequence of canine Na-dependent neutral amino acid transporter (ASCT2) and its distribution were determined. The sequence was 2,090 bp long and was predicted to encode 544 amino acid polypeptides. The amino acid sequence deduced from canine ASCT2 showed 90% similarity to that of humans and mice. Northern blot analysis revealed ASCT2 expression in the kidney, heart, lung and muscles, and Western blot analysis using anti-human ASCT2 antiserum detected the bands at 60 and 65 kDa in membrane protein of the lung. RT-PCR analysis revealed ASCT2 expression in all the tissues examined.

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The neutral amino acid transporter ASCT2 is overexpressed in human colorectal adenomas and carcinomas

Cited by 37 publications

References 0 publications

Putative Transport Mechanism and Intracellular Fate of Trans-1-Amino-3-¹⁸F-Fluorocyclobutanecarboxylic Acid in Human Prostate Cancer

Putative Transport Mechanism and Intracellular Fate of Trans-1-Amino-3-¹⁸F-Fluorocyclobutanecarboxylic Acid in Human Prostate Cancer

c-Myc is crucial for the expression of LAT1 in MIA Paca-2 human pancreatic cancer cells

cDNA Sequence and Tissue Distribution of Canine Na-Dependent Neutral Amino Acid Transporter 2 (ASCT 2)

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The neutral amino acid transporter ASCT2 is overexpressed in human colorectal adenomas and carcinomas

Cited by 37 publications

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Putative Transport Mechanism and Intracellular Fate of Trans-1-Amino-3-18F-Fluorocyclobutanecarboxylic Acid in Human Prostate Cancer

Putative Transport Mechanism and Intracellular Fate of Trans-1-Amino-3-18F-Fluorocyclobutanecarboxylic Acid in Human Prostate Cancer

c-Myc is crucial for the expression of LAT1 in MIA Paca-2 human pancreatic cancer cells

cDNA Sequence and Tissue Distribution of Canine Na-Dependent Neutral Amino Acid Transporter 2 (ASCT 2)

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Resources

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Putative Transport Mechanism and Intracellular Fate of Trans-1-Amino-3-¹⁸F-Fluorocyclobutanecarboxylic Acid in Human Prostate Cancer

Putative Transport Mechanism and Intracellular Fate of Trans-1-Amino-3-¹⁸F-Fluorocyclobutanecarboxylic Acid in Human Prostate Cancer