Inhibition of epithelial-mesenchymal transition in bladder cancer cells via modulation of mTOR signalling

Abstract

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.

Thymoquinone inhibits epithelial-mesenchymal transition in prostate cancer cells by negatively regulating the TGF-β/Smad2/3 signaling pathway

“…Meanwhile, other studies have demonstrated that thymoquinone decreased the expression of Twist1 at the transcriptional level, leading to the reversal of EMT in MDA-MB-435, BT549 and HeLa cells. In addition, thymoquinone downregulated N-cadherin, Snail and Slug expressions in bladder cancer T24 cells, which were partially in accordance with our results (20).…”

Thymoquinone inhibits the metastasis of renal cell cancer cells by inducing autophagy via AMPK/mTOR signaling pathway

“…Therefore, TQ has been regarded as a promising agent for numerous diseases. Previous studies have revealed that TQ may exhibit high anti‐tumor efficiency against various cancers, such as breast cancer, gastric cancer, cervical cancer, colon cancer, central nervous system cancer, ovarian cancer, prostate cancer, bladder cancer and renal cell cancer . It is well known that invasion and metastasis play vital roles in the progression of tumors.…”

“…Previous studies have revealed that TQ may exhibit high anti-tumor efficiency against various cancers, such as breast cancer, gastric cancer, cervical cancer, colon cancer, central nervous system cancer, ovarian cancer, prostate cancer, bladder cancer and renal cell cancer. [10][11][12][13][14][15][16][17][18] It is well known that invasion and metastasis play vital roles in the progression of tumors. Recent research has shown that TQ can inhibit metastasis and EMT in prostate cancer via the transforming growth factor-beta/Smad2/3 signaling pathway.…”

Thymoquinone, as an anticancer molecule: from basic research to clinical investigation

“…It has been evident that thymoquinone treatment inhibits TWIST1 promoter activity and decreases its expression in breast cancer cell lines; leading to the inhibition of epithelial-mesenchymal transition (EMT) mediated cancer cell migration, invasion and metastasis [ 51 ]. Along with interfering with EMT, thymoquinone also attenuated mTOR activity, and inhibited PI3K/Akt signaling in bladder cancer [ 52 , 53 ].…”