Mounting evidence suggests that signalling cross-talk plays a significant role in the regulation of epithelial–mesenchymal transition (EMT) in cancer cells. However, the complex network regulating the EMT in different cancer types has not been fully described yet which affects the development of novel therapeutic strategies. In the present study, we investigated the signalling pathways involved in EMT of bladder cancer cells and demonstrated the effects of two novel agents in the regulation of EMT. Myrtucommulone-A (MC-A) and thymoquinone (TQ) have been shown to possess anti-cancer properties. However, their targets in the regulation of cancer cell behavior are not well defined. Here, we defined the effects of two putative anti-cancer agents on bladder cancer cell migration and their possible intracellular targets in the regulation of EMT. Our results suggest that MC-A or TQ treatment affected N-cadherin, Snail, Slug, and β-catenin expressions and effectively attenuated mTOR activity. The downstream components in mTOR signalling were also affected. MC-A treatment resulted in the concomitant inhibition of extracellular matrix-regulated protein kinases 1 and 2 (ERK 1/2), p38 mitogen-activated protein kinase (MAPK) and Src activity. On the other hand, TQ treatment increased Src activity while exerting no effect on ERK 1/2 or p38 MAPK activity. Given the stronger inhibition of EMT-related markers in MC-A-treated samples, we concluded that this effect might be due to collective inhibition of multiple signalling pathways which result in a decrease in their cross-talk in bladder cancer cells. Overall, the data in this study proposes novel action mechanisms for MC-A or TQ in bladder cancer cells and highlights the potential use of these active compounds in the regulation of EMT.
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We are grateful to Dr. Maël Charpentier (Institut für Organische Chemie der Universität des Saarlandes in Saarbrücken, Germany) for providing MC-A.
Conflicts of interest
This study was supported by the grants from the The Scientific and Technological Research Council of Turkey (nos 115S042, 114S542 and 113S927).
Electronic supplementary material
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The effects of MC-A or TQ treatment on clonogenicity of T24 cells. MC-A, TQ or rapamycin treatment reduced colony formation in a dose dependent manner. MC-A, rapamycin and TQ reduced the colony size (a), number (b) and changed colony morphology (c) compared to the control cells (PDF 11713 kb)
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Iskender, B., Izgi, K., Hizar, E. et al. Inhibition of epithelial-mesenchymal transition in bladder cancer cells via modulation of mTOR signalling. Tumor Biol. 37, 8281–8291 (2016). https://doi.org/10.1007/s13277-015-4695-1
- Bladder cancer
- Epithelial–mesenchymal transition