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

Grant number: 15/16958-4
Support type:Regular Research Grants - Publications - Scientific article
Duration: October 01, 2015 - March 31, 2016
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Humberto Dellê
Grantee:Humberto Dellê
Home Institution: Universidade Nove de Julho (UNINOVE). Campus Vergueiro. São Paulo , SP, Brazil


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-b1 is believed to contribute to carcinoma development by modulating immunossupressive molecules, including IDO. In addition, TGF-b1 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-²1 in T24 human bladder carcinoma cells. When T24 cells were incubated with the IDO inhibitor (MT, 1-methyl-D-tryptophan), with TGF-²1, and with MT+TGF-²1, 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-b1. 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-b1 and MT is associated with EMT in T24 human bladder carcinoma cells. MT has potentiating effect in TGF-²1-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. (AU)