1-Methyl-D-tryptophan activates aryl hydrocarbon receptor, a pathway associated with bladder cancer progression
Abstract Background Indoleamine 2, 3-dioxygenase-1 (IDO1) is a promising target for immunotherapy in bladder cancer (BC). IDO1 breaks-down tryptophan to generate kynurenine derivatives, which may activate the aryl hydrocarbon receptor (AHR). AHR is an important target for carcinogens, but its associ...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2020-09-01
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| Series: | BMC Cancer |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12885-020-07371-6 |
| _version_ | 1818584651197841408 |
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| author | Luiz Henrique Gomes Matheus Stephanie Vanin Dalmazzo Rodrigo Barbosa Oliveira Brito Lucas Alves Pereira Robson José de Almeida Cleber Pinto Camacho Humberto Dellê |
| author_facet | Luiz Henrique Gomes Matheus Stephanie Vanin Dalmazzo Rodrigo Barbosa Oliveira Brito Lucas Alves Pereira Robson José de Almeida Cleber Pinto Camacho Humberto Dellê |
| author_sort | Luiz Henrique Gomes Matheus |
| collection | DOAJ |
| description | Abstract Background Indoleamine 2, 3-dioxygenase-1 (IDO1) is a promising target for immunotherapy in bladder cancer (BC). IDO1 breaks-down tryptophan to generate kynurenine derivatives, which may activate the aryl hydrocarbon receptor (AHR). AHR is an important target for carcinogens, but its association with BC progression was unknown. Two IDO1 inhibitors used in clinical trials are 1-methyl-D-tryptophan (MT) and INCB240360. Because MT is an aromatic hydrocarbon, it may be a ligand for AHR. We hypothesized that AHR could be associated with BC progression and that MT could activate AHR in BC. Methods BC patients (n = 165) were selected from the Gene Expression Omnibus database. A cut-off point for relative expression of AHR and cytochrome 450 enzymes (CYP1A1, CYP1A2, and CYP1B1; markers of AHR activation) was determined to compare with the grade, stage, and tumor progression. For in vitro experiments, RT4 (grade 1) and T24 (grade 3) BC cells were incubated with MT and INCB240360 to evaluate the expression of AHR and CYP1A1. Results AHR activation was associated with grade, stage, and progression of BC. T24 cells express more CYP1A1 than RT4 cells. Although IDO1 expression and kynurenine production are elevated in T24 cells concomitantly to CYP1A1 expression, IDO1 inhibitors were not able to decrease CYP1A1 expression, in contrast, MT significantly increased it in both cell lines. Conclusion In conclusion, it is rational to inhibit IDO1 in BC, among other factors because it contributes to AHR activation. However, MT needs to be carefully evaluated for BC because it is an AHR pathway agonist independently of its effects on IDO1. |
| first_indexed | 2024-12-16T08:24:34Z |
| format | Article |
| id | doaj.art-3745564a48204c20b4064e97f09746dc |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-12-16T08:24:34Z |
| publishDate | 2020-09-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Cancer |
| spelling | doaj.art-3745564a48204c20b4064e97f09746dc2022-12-21T22:38:01ZengBMCBMC Cancer1471-24072020-09-012011710.1186/s12885-020-07371-61-Methyl-D-tryptophan activates aryl hydrocarbon receptor, a pathway associated with bladder cancer progressionLuiz Henrique Gomes Matheus0Stephanie Vanin Dalmazzo1Rodrigo Barbosa Oliveira Brito2Lucas Alves Pereira3Robson José de Almeida4Cleber Pinto Camacho5Humberto Dellê6Molecular Innovation and Biotechnology Laboratory, Program in Medicine, Universidade Nove de Julho – UNINOVEMolecular Innovation and Biotechnology Laboratory, Program in Medicine, Universidade Nove de Julho – UNINOVEMolecular Innovation and Biotechnology Laboratory, Program in Medicine, Universidade Nove de Julho – UNINOVEMolecular Innovation and Biotechnology Laboratory, Program in Medicine, Universidade Nove de Julho – UNINOVEMolecular Innovation and Biotechnology Laboratory, Program in Medicine, Universidade Nove de Julho – UNINOVEMolecular Innovation and Biotechnology Laboratory, Program in Medicine, Universidade Nove de Julho – UNINOVEMolecular Innovation and Biotechnology Laboratory, Program in Medicine, Universidade Nove de Julho – UNINOVEAbstract Background Indoleamine 2, 3-dioxygenase-1 (IDO1) is a promising target for immunotherapy in bladder cancer (BC). IDO1 breaks-down tryptophan to generate kynurenine derivatives, which may activate the aryl hydrocarbon receptor (AHR). AHR is an important target for carcinogens, but its association with BC progression was unknown. Two IDO1 inhibitors used in clinical trials are 1-methyl-D-tryptophan (MT) and INCB240360. Because MT is an aromatic hydrocarbon, it may be a ligand for AHR. We hypothesized that AHR could be associated with BC progression and that MT could activate AHR in BC. Methods BC patients (n = 165) were selected from the Gene Expression Omnibus database. A cut-off point for relative expression of AHR and cytochrome 450 enzymes (CYP1A1, CYP1A2, and CYP1B1; markers of AHR activation) was determined to compare with the grade, stage, and tumor progression. For in vitro experiments, RT4 (grade 1) and T24 (grade 3) BC cells were incubated with MT and INCB240360 to evaluate the expression of AHR and CYP1A1. Results AHR activation was associated with grade, stage, and progression of BC. T24 cells express more CYP1A1 than RT4 cells. Although IDO1 expression and kynurenine production are elevated in T24 cells concomitantly to CYP1A1 expression, IDO1 inhibitors were not able to decrease CYP1A1 expression, in contrast, MT significantly increased it in both cell lines. Conclusion In conclusion, it is rational to inhibit IDO1 in BC, among other factors because it contributes to AHR activation. However, MT needs to be carefully evaluated for BC because it is an AHR pathway agonist independently of its effects on IDO1.http://link.springer.com/article/10.1186/s12885-020-07371-6Aryl hydrocarbon receptorIndoleamine 2, 3-dioxygenaseBladder cancerCytochrome P450 enzymes |
| spellingShingle | Luiz Henrique Gomes Matheus Stephanie Vanin Dalmazzo Rodrigo Barbosa Oliveira Brito Lucas Alves Pereira Robson José de Almeida Cleber Pinto Camacho Humberto Dellê 1-Methyl-D-tryptophan activates aryl hydrocarbon receptor, a pathway associated with bladder cancer progression BMC Cancer Aryl hydrocarbon receptor Indoleamine 2, 3-dioxygenase Bladder cancer Cytochrome P450 enzymes |
| title | 1-Methyl-D-tryptophan activates aryl hydrocarbon receptor, a pathway associated with bladder cancer progression |
| title_full | 1-Methyl-D-tryptophan activates aryl hydrocarbon receptor, a pathway associated with bladder cancer progression |
| title_fullStr | 1-Methyl-D-tryptophan activates aryl hydrocarbon receptor, a pathway associated with bladder cancer progression |
| title_full_unstemmed | 1-Methyl-D-tryptophan activates aryl hydrocarbon receptor, a pathway associated with bladder cancer progression |
| title_short | 1-Methyl-D-tryptophan activates aryl hydrocarbon receptor, a pathway associated with bladder cancer progression |
| title_sort | 1 methyl d tryptophan activates aryl hydrocarbon receptor a pathway associated with bladder cancer progression |
| topic | Aryl hydrocarbon receptor Indoleamine 2, 3-dioxygenase Bladder cancer Cytochrome P450 enzymes |
| url | http://link.springer.com/article/10.1186/s12885-020-07371-6 |
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