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 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.
Highlights
Urinary bladder cancer is the most common malignancy of the urinary system [1]
The concentration of kynurenine was markedly diminished after incubation with MT, TGF-β1, and MT + TGF-β1 (0.59 ± 0.12 μM, 0.29 ± 0.02 μM, and 0.38 ± 0.06 μM, respectively, vs. 3.45 ± 0.16 μM in the Control; p
We were able to induce epithelial-mesenchymal transition (EMT) in T24 cells with TGF-β1, and this effect correlates with downregulation of IDO
Summary
The most common form of human bladder cancer is non-muscle invasive (70% to 80%), 30% to 50% of these cases progress to a muscle-invasive form after repeated resections, which leads to cancer-specific death and metastasis [2]. Multiple mechanisms have been implicated in tumor invasiveness and metastasis, including the epithelial-mesenchymal transition (EMT). In this process, a polarized epithelial cell assumes a mesenchymal phenotype, which leads to a loss of cellular adhesion to the basement membrane, activation of motility and invasiveness, and production of extracellular-matrixdegrading enzymes [3]. TGF-β1 is an important inducer of EMT in several different types of tumors [4], including bladder cancer [5]. Certain genetic variations and increased plasma levels of TGF-β are potent predictors of bladder cancer risk [6,7]
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