The DOI matches its Crossref record; 54 of the 54 references it cites were found in a registry or an index.
A Variant of SLC1A5 Is a Mitochondrial Glutamine Transporter for Metabolic Reprogramming in Cancer Cells
Open accessAbstract
Glutamine is an essential nutrient that regulates energy production, redox homeostasis, and signaling in cancer cells. Despite the importance of glutamine in mitochondrial metabolism, the mitochondrial glutamine transporter has long been unknown. Here, we show that the SLC1A5 variant plays a critical role in cancer metabolic reprogramming by transporting glutamine into mitochondria. The SLC1A5 variant has an N-terminal targeting signal for mitochondrial localization. Hypoxia-induced gene expression of the SLC1A5 variant is mediated by HIF-2α. Overexpression of the SLC1A5 variant mediates glutamine-induced ATP production and glutathione synthesis and confers gemcitabine resistance to pancreatic cancer cells. SLC1A5 variant knockdown and overexpression alter cancer cell and tumor growth, supporting an oncogenic role. This work demonstrates that the SLC1A5 variant is a mitochondrial glutamine transporter for cancer metabolic reprogramming.
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In the citing paper
“For mitochondrial glutaminolysis, cytosolic glutamine must be transported through the inner mitochondrial membrane via the SLC1A5 variant, a mitochondrial glutamine transporter16.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [16]
In the citing paper
“the mitochondrial glutamine transporter, encoded by a transcript variant of the SLC1A5 gene, which encodes a well-known plasma membrane glutamine transporter, was only recently discovered16.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [16]
In the citing paper
“Although glutamate is the major downstream product of glutamine, glutamate supplementation during glutamine deprivation cannot rescue the impaired cell growth or mitochondrial respiration16,43–45, indicating that mitochondrial GLS-catalyzed cleavage of the gamma-nitrogen of glutamine is essential for glutaminolysis.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [16]
In the citing paper
“Hypoxic conditions promote the uptake of glutamine by increasing the levels of glutamine transporters such as SLC1A5, the SLC1A5 variant, and SLC38A216,65”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [16]
In the citing paper
“and the mitochondrial glutamine transporter is strongly associated with glutaminolysis-induced NADPH generation16.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [16]
In the citing paper
“Furthermore, redox modulation augmented by increased glutathione synthesis from glutamine was reported to be the mechanism of resistance to gemcitabine in pancreatic cancer cells16.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [16]
In the citing paper
“Impairing glutamine metabolism also induces sensitivity in gemcitabine-resistant pancreatic cancer cells16,84,85.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [16]
In the citing paper
“Indeed, experiments using uniformly labeled 13C-glutamine showed that glutathione was enriched with five 13C atoms in glutathione, suggesting that glutamine is the major source of glutathione16,57,60.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [16]
In the citing paper
“Recently, hypoxia-induced expression of the SLC1A5 variant was shown to be mediated by HIF-2α and to lead to metabolic reprogramming toward glutamine metabolism in pancreatic cancer cells16.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [16]
In the citing paper
“Intriguingly, this study regarding elevated glutamine metabolism in cancer cells also showed that glutaminolysis could in turn reinforce metabolic reprogramming, thus implying that glutamine metabolism plays a crucial role in tumorigenesis and tumor progression16”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [16]
In the citing paper
“Additionally, the level of the mitochondrial glutamine transporter controls the cellular ATP level stimulated by glutamine, suggesting that glutamine is an important energy source via mitochondrial glutaminolysis16.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [16]
In the citing paper
“in addition, the expression of the SLC1A5 variant affected the levels of metabolites derived from glucose metabolism, including lactate and ribulose-5-phosphate, the intermediate metabolites in the PPP16.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [16]
In the citing paper
“Recently, glutamine was shown to be a major fuel for mitochondrial oxygen consumption in pancreatic cancer cells”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [16]
In the citing paper
“Thus, as the SLC1A5 variant is the only currently known glutamine transporter in the mitochondrial inner membrane16”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [16]
In the citing paper
“Given the clinicopathological significance of SLC1A5201 and the observation that the level of the SLC1A5 variant is negatively correlated with prognosis in several cancer types16”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [16]
In the citing paper
“Conversely, suppression of the SLC1A5 variant, a mitochondrial glutamine transporter, is sufficient to inhibit tumor growth by impairing glutamine metabolism in pancreatic cancer cells16.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [16]
In the citing paper
“HIF‐2α‐induced expression of the glutamine transporter solute carrier family 1, member 5 (SLC1A5) mediates glutamine‐induced ATP production and glutathione synthesis and renders pancreatic cancer resistant to gemcitabine.”
From Hypoxia signaling in cancer: Implications for therapeutic interventions (2023) · cites this paper as [56]
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Metadata
- Authors
- Yoo, H. C., Park, S. J., Nam, M., Kang, J., Kim, K., Yeo, J. H., Kim, J.-K., Heo, Y., Lee, H. S., Lee, M. Y., Lee, C. W., Kang, J. S., Kim, Y.-H., Lee, J., Choi, J., Hwang, G.-S., Bang, S., & Han, J. M.
- Affiliations
- Yonsei University (KR)
- Korea Basic Science Institute (KR)
- National Cancer Center (KR)
- Korea Research Institute of Bioscience and Biotechnology (KR)
- Corresponding author
- Han, Jung Min
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2020-02
- Volume
- 31
- Issue
- 2
- Pages
- 267-283.e12
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W2995576736
- Cited by
- 449
- References
- 54
- Citations by year
- 2026: 65 · 2025: 78 · 2024: 87 · 2023: 67 · 2022: 67 · 2021: 55 · 2020: 29
- FWCI
- 12.03
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- KRIBB Repository (submittedVersion)
- YUHSpace (Yonsei University Medical Library) (submittedVersion, cc-by-nc-nd)
- Funders
- National Research Foundation of Korea
- Korea Basic Science Institute
- Ministry of Education (2018R1A6A1A03023718)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- glutamine transport, tumor metabolic reprogramming, mitochondrial targeting signal, HIF-2α, hypoxia, glutathione synthesis, ATP production, gemcitabine resistance, pancreatic cancer, tumor growth
- MeSH terms
- Tumor Hypoxia, Endothelial PAS Domain-Containing Protein 1, Animals, Female, Glutamine, Humans, Mice, Inbred BALB C, Mitochondria, Neoplasms, Minor Histocompatibility Antigens, Amino Acid Transport System ASC, Cell Line, Tumor, Mice, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins, Cellular Reprogramming
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