1-Methyl-D-tryptophan potentiates TGF-β-induced epithelial-mesenchymal transition in T24 human bladder cancer cells.
Immune escape and metastasis are the hallmarks of several types of cancer including bladder cancer. One of the mechanisms involved in these processes has been linked to indoleamine 2,3-dioxygenase (IDO). Although IDO is classically recognized for its immunomodulatory property, it has presented nonimmunological effects in some tumors. TGF-β1 is believed to contribute to carcinoma development by modulating immunossupressive molecules, including IDO. In addition, TGF-β1 induces the epithelial-mesenchymal transition (EMT), which is a critical step in the tumor invasiveness and metastasis. We investigated the role of MT and IDO modulation in the induction of EMT by TGF-β1 in T24 human bladder carcinoma cells. When T24 cells were incubated with the IDO inhibitor (MT, 1-methyl-D-tryptophan), with TGF-β1, and with MT+TGF-β1, a significant decrease of IDO expression and activity was observed. In addition, downregulation of e-cadherin and upregulation of n-cadherin and EMT transcription factors were induced by the treatments, confirming the induction of EMT. siRNA-mediated knockdown of IDO decreased e-cadherin expression, but had no effect on EMT transcription factors. In the scratch-wound assay, the heightened migration process was intensified when the cells were incubated with MT+TGF-β1. These effects were associated with a robust inhibition of Akt activation. After inoculation of T24 cells under the kidney capsule of Balb/c nude, the cells were positive for IDO in the center of the cell infiltrate, being negative in the periphery, where EMT is high. In conclusion, inhibition of IDO by TGF-β1 and MT is associated with EMT in T24 human bladder carcinoma cells. MT has potentiating effect in TGF-β1-induced EMT, independently of IDO. This nonimmunological effect of MT should be considered if IDO is the target to avoid immune escape in bladder cancer.
Programa de Pós-graduação em Medicina, Universidade Nove de Julho (UNINOVE), São Paulo, Brazil.
Rodrigo Barbosa Oliveira
RB
Brito
Programa de Pós-graduação em Medicina, Universidade Nove de Julho (UNINOVE), São Paulo, Brazil.
Camila Soares
CS
Malta
Programa de Pós-graduação em Medicina, Universidade Nove de Julho (UNINOVE), São Paulo, Brazil.
Diego Mota
DM
Souza
Programa de Pós-graduação em Medicina, Universidade Nove de Julho (UNINOVE), São Paulo, Brazil.
Luiz Henrique Gomes
LH
Matheus
Programa de Pós-graduação em Medicina, Universidade Nove de Julho (UNINOVE), São Paulo, Brazil.
Yves Silva Teles
YS
Matos
Programa de Pós-graduação em Medicina, Universidade Nove de Julho (UNINOVE), São Paulo, Brazil.
Chrisna Souza
CS
Silva
Programa de Pós-graduação em Medicina, Universidade Nove de Julho (UNINOVE), São Paulo, Brazil.
Janaína Mendes
JM
Ferreira
Lipids Laboratory (LIM-10), Endocrinology and Metabolism Division of Hospital das Clínicas, Faculty of Medical Sciences, University of São Paulo, São Paulo, Brazil.
Valeria Sutti
VS
Nunes
Programa de Pós-graduação em Biofotônica em Ciências da Saúde, Universidade Nove de Julho (UNINOVE), São Paulo, Brazil.
Cristiane Miranda
CM
França
Programa de Pós-graduação em Medicina, Universidade Nove de Julho (UNINOVE), São Paulo, Brazil.
Humberto
H
Dellê
D000818:Animals; D015820:Cadherins / Q000096:biosynthesis; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000276:immunology; D009362:Neoplasm Metastasis; D034741:RNA, Small Interfering; D053773:Transforming Growth Factor beta1 / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism*; D014364:Tryptophan / Q000008:administration & dosage* / Q000031:analogs & derivatives; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
D015820:Cadherins; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D034741:RNA, Small Interfering; D053773:Transforming Growth Factor beta1; D014364:Tryptophan