Expression profile of the amino acid transporters
            <scp>SLC</scp>
            7A5,
            <scp>SLC</scp>
            7A7,
            <scp>SLC</scp>
            7A8 and the enzyme
            <scp>TDO</scp>
            2 in basal cell carcinoma

Tina, Elisabet; Prosén, S.; Lennholm, S.; Gasparyan, G. H.; Lindberg, Magnus; Eremo, Anna Göthlin

doi:10.1111/bjd.16905

Cited by 26 publications

(6 citation statements)

References 34 publications

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“…Obtained data revealed that in rectal cancer samples the kynurenine pathway was characterized by TDO2 overexpression, while IDO1 expression remained practically unchanged (using a 1.5-fold ratio criterion). These data are consistent with others reported in literature, in which TDO2 expression in several human tumor cell lines and tissues has been demonstrated ( 26 , 28 , 40 – 42 ). Similarly, a rise in the calculated enzymatic activity (KYN/TRP * 1,000) in rectal cancer tissues compared to mucosa was detected (mean activity: 111 and 230 for healthy mucosa and rectal cancer, respectively; p < 0.05, Wilcoxon signed-rank test).…”

Section: Resultssupporting

confidence: 94%

Tryptophan Catabolism and Response to Therapy in Locally Advanced Rectal Cancer (LARC) Patients

et al. 2020

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In locally advanced rectal cancer patients (LARC), preoperative chemoradiation improves local control and sphincter preservation. The response rate to treatment varies substantially between 20 and 30%, and it is an important prognostic factor. Indeed, nonresponsive patients are subjected to higher rates of local and distant metastases, and worse survival compared to patients with complete response. In the search of predictive biomarkers for response prediction to therapy in LARC patients, we found increased plasma tryptophan levels in nonresponsive patients. On the basis of plasma levels of 5-hydroxy-tryptophan and kynurenine, the activities of tryptophan 5-hydroxylase 1 (TPH1) and indoleamine-2,3-dioxygenases 1 (IDO1)/tryptophan-2,3dioxygenase (TDO2) have been obtained and data have been correlated with gene expression profiles. We demonstrated that TDO2 overexpression in nonresponsive patients correlates with kynurenine plasma levels. Finally, through the gene expression and targeted metabolomic analysis in paired healthy mucosa-rectal cancer tumor samples, we evaluated the impact of tryptophan catabolism at tissue level in responsive and nonresponsive patients.

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Section: Resultssupporting

confidence: 94%

Tryptophan Catabolism and Response to Therapy in Locally Advanced Rectal Cancer (LARC) Patients

et al. 2020

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“… 64 , 73 Specifically, TDO2 has been reported to be expressed in malignant glioma, hepatic carcinoma, non-small cell lung carcinoma (NSCLC), RCC, ovarian carcinoma, breast cancer, bladder cancer, basal cell carcinoma and melanoma. 7 , 15 , 74 – 76 In co-cultures of glioblastoma cells with mixed leucocyte reactions (as an assay of T-cell competence), tumour cell TDO2 expression suppressed T-cell proliferation via the production of Kyn. 7 This immunosuppressive effect was also observed in vivo, as TDO2 expression inhibited immune infiltration into gliomas 7 and prevented tumour rejection in immunised mice.…”

Section: Trp-catabolising Enzymes (Tce)mentioning

confidence: 99%

The therapeutic potential of targeting tryptophan catabolism in cancer

et al. 2019

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Based on its effects on both tumour cell intrinsic malignant properties as well as anti-tumour immune responses, tryptophan catabolism has emerged as an important metabolic regulator of cancer progression. Three enzymes, indoleamine-2,3-dioxygenase 1 and 2 (IDO1/2) and tryptophan-2,3-dioxygenase (TDO2), catalyse the first step of the degradation of the essential amino acid tryptophan (Trp) to kynurenine (Kyn). The notion of inhibiting IDO1 using small-molecule inhibitors elicited high hopes of a positive impact in the field of immuno-oncology, by restoring anti-tumour immune responses and synergising with other immunotherapies such as immune checkpoint inhibition. However, clinical trials with IDO1 inhibitors have yielded disappointing results, hence raising many questions. This review will discuss strategies to target Trp-degrading enzymes and possible down-stream consequences of their inhibition. We aim to provide comprehensive background information on Trp catabolic enzymes as targets in immuno-oncology and their current state of development. Details of the clinical trials with IDO1 inhibitors, including patient stratification, possible effects of the inhibitors themselves, effects of pre-treatments and the therapies the inhibitors were combined with, are discussed and mechanisms proposed that might have compensated for IDO1 inhibition. Finally, alternative approaches are suggested to circumvent these problems.

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“…From a medical point of view, LAT2 is expressed in several tissues as the brain, heart, small intestine, lung, spleen, liver, prostate, kidney, ovary, testis, skeletal muscle, placenta, and fetal liver [ 1 ]. Whereas the loss of LAT2-dependent transport function is attributed to age-related hearing loss, renal aminoaciduria, and cataract formation [ 1 , 13 , 14 , 15 ], an elevated expression level of LAT2 is linked to cancer [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

Sub-Nanometer Cryo-EM Density Map of the Human Heterodimeric Amino Acid Transporter 4F2hc-LAT2

Jeckelmann

Fotiadis

2020

IJMS

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Heterodimeric amino acid transporters (HATs) are protein complexes mediating the transport of amino acids and derivatives thereof across biological membranes. HATs are composed of two subunits, a heavy and a light chain subunit belonging to the solute carrier (SLC) families SLC3 and SLC7. The human HAT 4F2hc-LAT2 is composed of the type-II membrane N-glycoprotein 4F2hc (SCL3A2) and the L-type amino acid transporter LAT2 (SLC7A8), which are covalently linked to each other by a conserved disulfide bridge. Whereas LAT2 catalyzes substrate transport, 4F2hc is important for the successful trafficking of the transporter to the plasma membrane. The overexpression, malfunction, or absence of 4F2hc-LAT2 is associated with human diseases, and therefore, this heterodimeric complex represents a potential drug target. The recombinant human 4F2hc-LAT2 can be functionally overexpressed in the methylotrophic yeast Pichia pastoris, and the protein can be purified. Here, we present the cryo-EM density map of the human 4F2hc-LAT2 amino acid transporter at sub-nanometer resolution. A homology model of 4F2hc-LAT2 in the inward-open conformation was generated and fitted into the cryo-EM density and analyzed. In addition, disease-causing point mutations in human LAT2 were mapped on the homology model of 4F2hc-LAT2, and the possible functional implications on the molecular level are discussed.

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Expression profile of the amino acid transporters SLC 7A5, SLC 7A7, SLC 7A8 and the enzyme TDO 2 in basal cell carcinoma

Abstract: This study highlights the upregulation of SLC7A5, SLC7A8 and TDO2 in BCC compared with nontumour skin. Our findings imply that amino acid transporters may be further explored as potential targets for future medical treatment.

Cited by 26 publications

References 34 publications

Tryptophan Catabolism and Response to Therapy in Locally Advanced Rectal Cancer (LARC) Patients

Tryptophan Catabolism and Response to Therapy in Locally Advanced Rectal Cancer (LARC) Patients

The therapeutic potential of targeting tryptophan catabolism in cancer

Sub-Nanometer Cryo-EM Density Map of the Human Heterodimeric Amino Acid Transporter 4F2hc-LAT2

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