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[1-methyl-D-tryptophan potentiates TGF-²-induced epithelial-mesenchymal transition in T24 human bladder cancer cells]

Original in Portuguese: 1-methyl-D-tryptophan potentiates TGF-²-induced epithelial-mesenchymal transition in T24 human bladder cancer cells

Funder: São Paulo Research Foundation

Funding period
0
Funding amount
Abstract
[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 associated with indoleamine 2,3-dioxigenase (IDO). Although IDO is classically recognized for its immunomodulatory property, the enzyme has shown non-immunological effects in some tumors. TGF-b1 is believed to contribute to the development of carcinoma through the modulation of immunosuppressive molecules, including IDO. In addition, TGF-b1 induces epithelial-mesenchymal transition (EMT), which is a critical step in the capacity for tumor invasion and metastasis. The objective was to investigate the role of the IDO inhibitor (1-methil-tryptophan) in the modulation of EMT induction by TGF-²1 in human bladder carcinoma cells T24. When T24 cells were incubated with the IDO inhibitor, with TGF-²1, and with MT + TGF-²1, a significant decrease in IDO expression and activity was observed. In addition, negative regulation of E-cadherin and positive regulation of N-cadherin and transcription factors for EMT were induced by the treatments, confirming the induction of EMT. IDO's siRNA-mediated knockdown led to decreased E-cadherin expression, but had no effect on EMT transcription factors. The migration process evaluated "in vitro" was intensified when the cells were incubated with MT + TGF-b1. These effects have been associated with an inhibition of Akt pathway activation. After inoculation of T24 cells under the kidney capsule of nude Balb / c mice, IDO positive cells were particularly in the center of the cell infiltrate, being negative in the periphery, where EMT was high. In conclusion, the inhibition of IDO by TGF-b1 and MT is associated with EMT in human bladder carcinoma cells. MT has a potentiating effect on EMT induced by TGF-²1, regardless of IDO. This non-immunological effect of MT should be considered if IDO is the target to prevent immune escape in bladder cancer. (AU)]
Original in Portuguese
O escape imune e a metástase são as marcas de vários tipos de câncer, incluindo câncer de bexiga. Um dos mecanismos envolvidos nestes processos tem sido associado à indoleamina 2,3-dioxigenase (IDO). Embora a IDO seja classicamente reconhecida por sua propriedade imunomoduladora, a enzima tem apresentado efeitos não-imunológicos em alguns tumores. Acredita-se que TGF-b1 contribuir para o desenvolvimento de carcinoma através da modulação de moléculas imunossupressoras, incluindo IDO. Além disso, o TGF-b1 induz a transição epitelial-mesenquimal (EMT), que é um passo crítico na capacidade de invasão tumoral e metástases. O objetivo foi investigar o papel do inibidor da IDO (1-methil-triptofan) na modulação da indução de EMT por TGF-²1 em células de carcinoma da bexiga humana T24. Quando as células T24 foram incubadas com o inibidor da IDO, com TGF-²1, e com MT + TGF-²1, foi observada uma diminuição significativa da expressão e atividade da IDO. Além disso, a regulação negativa de E-caderina e a regulação positiva de N-caderina e fatores de transcrição para EMT foram induzidos pelos tratamentos, confirmando a indução de EMT. knockdown mediada por siRNA da IDO levou à diminuição da expressão da E-caderina, mas não teve nenhum efeito sobre os factores de transcrição EMT. O processo de migração avaliado "in vitro" foi intensificado quando as células foram incubadas com MT + TGF-b1. Estes efeitos foram associados a uma inibição da ativação da via Akt. Após a inoculação de células T24 sob a cápsula do rim de camundongos Balb/c nude, as células positivas para IDO estavam particularmente no centro do infiltrado celular, sendo negativo na periferia, onde EMT foi alta. Em conclusão, a inibição de IDO por TGF-b1 e MT associa-se com EMT em células de carcinoma da bexiga humana. MT tem efeito potenciador na EMT induzida por TGF-²1, independentemente da IDO. Este efeito não-imunológico de MT deve ser considerada se IDO é o alvo para evitar escape imune no câncer de bexiga. (AU)
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System

Categories
  • FOR (ANZSRC)

    1112 Oncology and Carcinogenesis

  • RCDC

    Cancer

  • RCDC

    Genetics

  • RCDC

    Urologic Diseases

  • HRCS HC

    Cancer

  • HRCS RAC

    2.1 Biological and endogenous factors

  • Health Research Areas

    Biomedical

  • Broad Research Areas

    Basic Science