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

Bröer, Stefan

doi:10.3390/ijms21176156

Cited by 75 publications

(69 citation statements)

References 128 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Due to the rapid proliferation, cancer cells have increased demand for amino acids in maintaining one-carbon metabolism, signal pathway, as well as the synthesis of nucleotide and protein [ 12 , 13 ]. The expression levels of amino acid transporters are closely associated with tumor size, pathological grade and distant metastasis [ 14 , 15 , 16 ]. Thus, increasing investigations have demonstrated the feasibility of amino acid transporters as a component of anti-cancer therapy.…”

Section: Introductionmentioning

confidence: 99%

The Harmonious Interplay of Amino Acid and Monocarboxylate Transporters Induces the Robustness of Cancer Cells

Yoshida

2021

Metabolites

View full text Add to dashboard Cite

There is a growing body of evidence that metabolic reprogramming contributes to the acquisition and maintenance of robustness associated with malignancy. The fine regulation of expression levels of amino acid and monocarboxylate transporters enables cancer cells to exhibit the metabolic reprogramming that is responsible for therapeutic resistance. Amino acid transporters characterized by xCT (SLC7A11), ASCT2 (SLC1A5), and LAT1 (SLC7A5) function in the uptake and export of amino acids such as cystine and glutamine, thereby regulating glutathione synthesis, autophagy, and glutaminolysis. CD44 variant, a cancer stem-like cell marker, stabilizes the xCT antiporter at the cellular membrane, and tumor cells positive for xCT and/or ASCT2 are susceptible to sulfasalazine, a system Xc(-) inhibitor. Inhibiting the interaction between LAT1 and CD98 heavy chain prevents activation of the mammalian target of rapamycin (mTOR) complex 1 by glutamine and leucine. mTOR signaling regulated by LAT1 is a sensor of dynamic alterations in the nutrient tumor microenvironment. LAT1 is overexpressed in various malignancies and positively correlated with poor clinical outcome. Metabolic reprogramming of glutamine occurs often in cancer cells and manifests as ASCT2-mediated glutamine addiction. Monocarboxylate transporters (MCTs) mediate metabolic symbiosis, by which lactate in cancer cells under hypoxia is exported through MCT4 and imported by MCT1 in less hypoxic regions, where it is used as an oxidative metabolite. Differential expression patterns of transporters cause functional intratumoral heterogeneity leading to the therapeutic resistance. Therefore, metabolic reprogramming based on these transporters may be a promising therapeutic target. This review highlights the pathological function and therapeutic targets of transporters including xCT, ASCT2, LAT1, and MCT.

show abstract

Section: Introductionmentioning

confidence: 99%

The Harmonious Interplay of Amino Acid and Monocarboxylate Transporters Induces the Robustness of Cancer Cells

Yoshida

2021

Metabolites

View full text Add to dashboard Cite

show abstract

“…Altogether, our model proposes that the three transporters, SLC1A5, SLC7A5, and SLC38A2, form a cooperative system in reprogramming the pro‐tumor metabolism. The collaboration of amino acid transporters may be further extended to other SLC proteins, such as SLC7A11, SLC7A8, SLC38A2, etc., especially in the context of cancer cells as recently reviewed [39] …”

Section: Discussionmentioning

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

View full text Add to dashboard Cite

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.

show abstract

“…It is conceivable that amino acid transporters play important roles in regulating drug sensitivity/resistance in amino acid starvation therapies; after all, they control the inputs of cellular amino acid contents for cell growth. Here are just a few examples: SNAT1 (SLC38A1), SNAT2 (SLC38A2), and ASCT2 (SLC1A5) are the major Gln transporters in cancer cells [ 112 ]. SNAT2 senses the availability of substrate and increases its expression when cellular amino acid substrates are low [ 113 ].…”

Section: Mechanisms Of Drug Resistancementioning

confidence: 99%

Targeting the Proline–Glutamine–Asparagine–Arginine Metabolic Axis in Amino Acid Starvation Cancer Therapy

et al. 2021

View full text Add to dashboard Cite

Proline, glutamine, asparagine, and arginine are conditionally non-essential amino acids that can be produced in our body. However, they are essential for the growth of highly proliferative cells such as cancers. Many cancers express reduced levels of these amino acids and thus require import from the environment. Meanwhile, the biosynthesis of these amino acids is inter-connected but can be intervened individually through the inhibition of key enzymes of the biosynthesis of these amino acids, resulting in amino acid starvation and cell death. Amino acid starvation strategies have been in various stages of clinical applications. Targeting asparagine using asparaginase has been approved for treating acute lymphoblastic leukemia. Targeting glutamine and arginine starvations are in various stages of clinical trials, and targeting proline starvation is in preclinical development. The most important obstacle of these therapies is drug resistance, which is mostly due to reactivation of the key enzymes involved in biosynthesis of the targeted amino acids and reprogramming of compensatory survival pathways via transcriptional, epigenetic, and post-translational mechanisms. Here, we review the interactive regulatory mechanisms that control cellular levels of these amino acids for amino acid starvation therapy and how drug resistance is evolved underlying treatment failure.

show abstract

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

Cited by 75 publications

References 128 publications

The Harmonious Interplay of Amino Acid and Monocarboxylate Transporters Induces the Robustness of Cancer Cells

The Harmonious Interplay of Amino Acid and Monocarboxylate Transporters Induces the Robustness of Cancer Cells

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

Targeting the Proline–Glutamine–Asparagine–Arginine Metabolic Axis in Amino Acid Starvation Cancer Therapy

Contact Info

Product

Resources

About