The role of ASCT2 in cancer: A review

Liu, Yang; Zhao, Tingli; Li, Zhengzheng; Wang, Lai; Yuan, Shengtao; Sun, Li

doi:10.1016/j.ejphar.2018.07.007

Cited by 121 publications

(82 citation statements)

References 41 publications

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“…GTK and ω-amidase are also present in normal and cancerous human bladder epithelial cells and in normal and cancerous human prostate epithelial cells [1,7] (present work). We suggest that the relatively high concentrations of GTK and ω-amidase in epithelial tissues, the high concentration of glutamine in the circulation (~0.5-0.8 mM [40]) and the presence of high capacity glutamine transporters (e.g., [41,42]) are important for maintaining cellular nitrogen and energy homeostasis. The glutaminase II pathway may be especially important in rapidly dividing cells that are known to consume glutamine as an important energy source, such as enterocytes [43], lymphocytes [44], and bone cells [45].…”

Section: The Glutaminase II Pathway Permits the Formation Of A-ketoglmentioning

confidence: 97%

“…Our findings [1,7] (present work) together with the findings of Udupa et al [9] suggest that the glutaminase II pathway is also important in rapidly dividing cancer cells. Interestingly, the glutamine transporter ASCT2 is strongly expressed in highly proliferative cells, including cancer cells [41,42].…”

Section: The Glutaminase II Pathway Permits the Formation Of A-ketoglmentioning

confidence: 99%

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High Levels of Glutaminase II Pathway Enzymes in Normal and Cancerous Prostate Suggest a Role in ‘Glutamine Addiction’

Dorai

Pinto

et al. 2019

Biomolecules

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Many tumors readily convert l-glutamine to α-ketoglutarate. This conversion is almost invariably described as involving deamidation of l-glutamine to l-glutamate followed by a transaminase (or dehydrogenase) reaction. However, mammalian tissues possess another pathway for conversion of l-glutamine to α-ketoglutarate, namely the glutaminase II pathway: l-Glutamine is transaminated to α-ketoglutaramate, which is then deamidated to α-ketoglutarate by ω-amidase.Here we show that glutamine transaminase and ω-amidase specific activities are high in normal rat prostate. Immunohistochemical analyses revealed that glutamine transaminase K (GTK) and ω-amidase are present in normal and cancerous human prostate and that expression of these enzymes increases in parallel with aggressiveness of the cancer cells. Our findings suggest that the glutaminase II pathway is important in providing anaplerotic carbon to the tricarboxylic acid (TCA) cycle, closing the methionine salvage pathway, and in the provision of citrate carbon in normal and cancerous prostate. Finally, our data also suggest that selective inhibitors of GTK and/or ω-amidase may be clinically important for treatment of prostate cancer. In conclusion, the demonstration of a prominent glutaminase II pathway in prostate cancer cells and increased expression of the pathway with increasing aggressiveness of tumor cells provides a new perspective on 'glutamine addiction' in cancers.

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Section: The Glutaminase II Pathway Permits the Formation Of A-ketoglmentioning

confidence: 97%

Section: The Glutaminase II Pathway Permits the Formation Of A-ketoglmentioning

confidence: 99%

High Levels of Glutaminase II Pathway Enzymes in Normal and Cancerous Prostate Suggest a Role in ‘Glutamine Addiction’

Dorai

Pinto

et al. 2019

Biomolecules

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“…Thus neutral amino acid transport is crucial for cancer cells. For many years, the research community has focused on three transporters, namely ASCT2 (SLC1A5) [30,31], LAT1 (SLC7A5) [32,33], and xCT (SLC7A11) [11]. The main reason for the interest in ASCT2 and LAT1 is the upregulation of these two transporters in many cancer cells [31,34].…”

Section: Wherementioning

confidence: 99%

Amino Acid Transporters as Targets for Cancer Therapy: Why, Where, When, and How

Bröer

2020

IJMS

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Amino acids are indispensable for the growth of cancer cells. This includes essential amino acids, the carbon skeleton of which cannot be synthesized, and conditionally essential amino acids, for which the metabolic demands exceed the capacity to synthesize them. Moreover, amino acids are important signaling molecules regulating metabolic pathways, protein translation, autophagy, defense against reactive oxygen species, and many other functions. Blocking uptake of amino acids into cancer cells is therefore a viable strategy to reduce growth. A number of studies have used genome-wide silencing or knock-out approaches, which cover all known amino acid transporters in a large variety of cancer cell lines. In this review, these studies are interrogated together with other databases to identify vulnerabilities with regard to amino acid transport. Several themes emerge, such as synthetic lethality, reduced redundancy, and selective vulnerability, which can be exploited to stop cancer cell growth.

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“…[5] Instead, we support the conclusions of Bröer et al, who reported that instead of SLC1A5, SLC38A1 and SLC38A2 are the essential transporters sustaining glutaminolysis in cancer cells. [14] Overexpression of SLC38A2, but not SLC1A5, is a pan-cancer high-risk indicator of cancer prognosis While SLC1A5 has been widely considered as a risk factor in many cancer types, [10] the association of SLC38A2 up-regulation and cancer progression is less documented in the literature. According to our NMR metabolic data, we speculated that cancer patients who possess high expression of SLC38A2 may be susceptible to poor prognosis due to the enhanced uptake of EAAs and glutaminolysis activity.…”

Section: Slc38a2 and Slc1a5 Overexpression Showed Opposite Effects Onmentioning

confidence: 99%

“…[7] SLC1A5 expression can be induced by the MYC oncogene, [8][9] and it has been found that SLC1A5 is over-expressed in several cancers with poor patient prognosis. [10] Consequently, SLC1A5 is often considered a major transporter involved in glutamine uptake. [5] Moreover, it was reported that the glutamine imported by SLC1A5 can be exchanged for EAAs via SLC7A5, which in turn activates the mTOR pathway.…”

Section: Introductionmentioning

confidence: 99%

SLC38A2 Overexpression Induces a Cancer‐like Metabolic Profile and Cooperates with SLC1A5 in Pan‐cancer Prognosis

Huang

Chang

Lin

et al. 2020

Chemistry An Asian Journal

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Cancer cells have dramatically increased demands for energy as well as biosynthetic precursors to fuel their restless growth. Enhanced glutaminolysis is a hallmark of cancer metabolism which fulfills these needs. Two glutamine transporters, SLC1A5 and SLC38A2, have been previously reported to promote glutaminolysis in cancer with controversial perspectives. In this study, we harnessed the proximity labeling reaction to map the protein interactome using mass spectrometry-based proteomics and discovered a potential protein-protein interaction between SLC1A5 and SLC38A2. The SLC1A5/SLC38A2 interaction was further confirmed by bimolecular fluorescence complementation assay. We further investigated the metabolic influence of SLC1A5 and SLC38A2 overexpression in human cells, respectively, and found that only SLC38A2, but not SLC1A5, resulted in a cancer-like metabolic profile, where the intracellular concentrations of essential amino acids and lactate were significantly increased as quantified by nuclear magnetic resonance spectroscopy. Finally, we analyzed the 5-year survival rates in a large pancancer cohort and found that the SLC1A5 hi /SLC38A2 lo group did not relate to a poor survival rate, whereas the SLC1A5 lo / SLC38A2 hi group significantly aggravated the lethality. Intriguingly, the SLC1A5 hi /SLC38A2 hi group resulted in an even worse prognosis, suggesting a cooperative effect between SLC1A5 and SCL38A2. Our data suggest that SLC38A2 plays a dominant role in reprogramming the cancer-like metabolism and promoting the cancer progression, whereas SLC1A5 may augment this effect when co-overexpressed with SLC38A2. We propose a model to explain the relationship between SLC1A5, SLC38A2 and SCL7A5, and discuss their impact on glutaminolysis and mTOR signaling.

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The role of ASCT2 in cancer: A review

Cited by 121 publications

References 41 publications

High Levels of Glutaminase II Pathway Enzymes in Normal and Cancerous Prostate Suggest a Role in ‘Glutamine Addiction’

High Levels of Glutaminase II Pathway Enzymes in Normal and Cancerous Prostate Suggest a Role in ‘Glutamine Addiction’

Amino Acid Transporters as Targets for Cancer Therapy: Why, Where, When, and How

SLC38A2 Overexpression Induces a Cancer‐like Metabolic Profile and Cooperates with SLC1A5 in Pan‐cancer Prognosis

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