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Glutamine transporters as pharmacological targets: From function to drug design.

ABSTRACT: Among the different targets of administered drugs, there are membrane transporters that play also a role in drug delivery and disposition. Moreover, drug-transporter interactions are responsible for off-target effects of drugs underlying their toxicity. The improvement of the drug design process is subjected to the identification of those membrane transporters mostly relevant for drug absorption, delivery and side effect production. A peculiar group of proteins with great relevance to pharmacology is constituted by the membrane transporters responsible for managing glutamine traffic in different body districts. The interest around glutamine metabolism lies in its physio-pathological role; glutamine is considered a conditionally essential amino acid because highly proliferative cells have an increased request of glutamine that cannot be satisfied only by endogenous synthesis. Then, glutamine transporters provide cells with this special nutrient. Among the glutamine transporters, SLC1A5, SLC6A14, SLC6A19, SLC7A5, SLC7A8 and some members of SLC38 family are the best characterized, so far, in both physiological and pathological conditions. Few 3D structures have been solved by CryoEM; other structural data on these transporters have been obtained by computational analysis. Interactions with drugs have been described for several transporters of this group. For some of them, the studies are at an advanced stage, for others, the studies are still in nuce and novel biochemical findings open intriguing perspectives.

SUBMITTER: Scalise M

PROVIDER: S-EPMC7193454 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Glutamine transporters as pharmacological targets: From function to drug design.

Scalise Mariafrancesca M Pochini Lorena L Galluccio Michele M Console Lara L Indiveri Cesare C

Asian journal of pharmaceutical sciences 20200305 2

Among the different targets of administered drugs, there are membrane transporters that play also a role in drug delivery and disposition. Moreover, drug-transporter interactions are responsible for off-target effects of drugs underlying their toxicity. The improvement of the drug design process is subjected to the identification of those membrane transporters mostly relevant for drug absorption, delivery and side effect production. A peculiar group of proteins with great relevance to pharmacolo ...[more]

PMID: 32373200

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Project description:The retention and cellular internalization of drug delivery systems and theranostics for cancer therapy can be improved by targeting molecules. Since an increased uptake of riboflavin was reported for various cancers, riboflavin and its derivatives may be promising binding moieties to trigger internalization via the riboflavin transporters (RFVT) 1, 2, and 3. Riboflavin is a vitamin with pivotal role in energy metabolism and indispensable for cellular growth. In previous preclinical studies on mice, we showed the target-specific accumulation of riboflavin-functionalized nanocarriers in cancer cells. Although the uptake mechanism of riboflavin has been studied for over a decade, little is known about the riboflavin transporters and their expression on cancer cells, tumor stroma, and healthy tissues. Furthermore, evidence is lacking concerning the representativeness of the preclinical findings to the situation in humans. In this study, we investigated the expression pattern of riboflavin transporters in human squamous cell carcinoma (SCC), melanoma and luminal A breast cancer samples, as well as in healthy skin, breast, aorta, and kidney tissues. Low constitutive expression levels of RFVT1-3 were found on all healthy tissues, while RFVT2 and 3 were significantly overexpressed in melanoma, RFVT1 and 3 in luminal A breast cancer and RFVT1-3 in SCC. Correspondingly, the SCC cell line A431 was highly positive for all RFVTs, thus qualifying as suitable in vitro model. In contrast, activated endothelial cells (HUVEC) only presented with a strong expression of RFVT2, and HK2 kidney cells only with a low constitutive expression of RFVT1-3. Functional in vitro studies on A431 and HK2 cells using confocal microscopy showed that riboflavin uptake is mostly ATP dependent and primarily driven by endocytosis. Furthermore, riboflavin is partially trafficked to the mitochondria. Riboflavin uptake and trafficking was significantly higher in A431 than in healthy kidney cells. Thus, this manuscript supports the hypothesis that addressing the riboflavin internalization pathway may be highly valuable for tumor targeted drug delivery.

Project description:Glutamine together with glucose is essential for body's homeostasis. It is the most abundant amino acid and is involved in many biosynthetic, regulatory and energy production processes. Several membrane transporters which differ in transport modes, ensure glutamine homeostasis by coordinating its absorption, reabsorption and delivery to tissues. These transporters belong to different protein families, are redundant and ubiquitous. Their classification, originally based on functional properties, has recently been associated with the SLC nomenclature. Function of glutamine transporters is studied in cells over-expressing the transporters or, more recently in proteoliposomes harboring the proteins extracted from animal tissues or over-expressed in microorganisms. The role of the glutamine transporters is linked to their transport modes and coupling with Na(+) and H(+). Most transporters share specificity for other neutral or cationic amino acids. Na(+)-dependent co-transporters efficiently accumulate glutamine while antiporters regulate the pools of glutamine and other amino acids. The most acknowledged glutamine transporters belong to the SLC1, 6, 7, and 38 families. The members involved in the homeostasis are the co-transporters B0AT1 and the SNAT members 1, 2, 3, 5, and 7; the antiporters ASCT2, LAT1 and 2. The last two are associated to the ancillary CD98 protein. Some information on regulation of the glutamine transporters exist, which, however, need to be deepened. No information at all is available on structures, besides some homology models obtained using similar bacterial transporters as templates. Some models of rat and human glutamine transporters highlight very similar structures between the orthologs. Moreover the presence of glycosylation and/or phosphorylation sites located at the extracellular or intracellular faces has been predicted. ASCT2 and LAT1 are over-expressed in several cancers, thus representing potential targets for pharmacological intervention.

Dataset Information

Glutamine transporters as pharmacological targets: From function to drug design.

Publications

Glutamine transporters as pharmacological targets: From function to drug design.

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