title: 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.
authors.affiliation: Department of Medical Biology, Faculty of Medicine, Erciyes University, 38039, Melikgazi, Kayseri, Turkey. banu.iskender@yahoo.com.|Betul-Ziya Eren Genome and Stem Cell Centre, Erciyes University, 38039, Melikgazi, Kayseri, Turkey. banu.iskender@yahoo.com.
authors.forename: Banu
authors.initials: B
authors.lastname: Iskender
authors.affiliation: Department of Medical Biochemistry, Faculty of Medicine, Erciyes University, 38039, Melikgazi, Kayseri, Turkey.|Betul-Ziya Eren Genome and Stem Cell Centre, Erciyes University, 38039, Melikgazi, Kayseri, Turkey.
authors.forename: Kenan
authors.initials: K
authors.lastname: Izgi
authors.affiliation: Department of Medical Biology, Faculty of Medicine, Erciyes University, 38039, Melikgazi, Kayseri, Turkey.|Betul-Ziya Eren Genome and Stem Cell Centre, Erciyes University, 38039, Melikgazi, Kayseri, Turkey.
authors.forename: Esra
authors.initials: E
authors.lastname: Hizar
authors.affiliation: Universität des Saarlandes, Organische Chemie II, Geb. C4.2, 66123, Saarbrücken, Germany.
authors.forename: Johann
authors.initials: J
authors.lastname: Jauch
authors.affiliation: Department of Medical Biochemistry, Faculty of Medicine, Erciyes University, 38039, Melikgazi, Kayseri, Turkey.|Betul-Ziya Eren Genome and Stem Cell Centre, Erciyes University, 38039, Melikgazi, Kayseri, Turkey.
authors.forename: Aslihan
authors.initials: A
authors.lastname: Arslanhan
authors.affiliation: Department of Medical Biochemistry, Faculty of Medicine, Erciyes University, 38039, Melikgazi, Kayseri, Turkey.|Betul-Ziya Eren Genome and Stem Cell Centre, Erciyes University, 38039, Melikgazi, Kayseri, Turkey.
authors.forename: Esra Hilal
authors.initials: EH
authors.lastname: Yuksek
authors.affiliation: Department of Medical Biology, Faculty of Medicine, Erciyes University, 38039, Melikgazi, Kayseri, Turkey.|Betul-Ziya Eren Genome and Stem Cell Centre, Erciyes University, 38039, Melikgazi, Kayseri, Turkey.
authors.forename: Halit
authors.initials: H
authors.lastname: Canatan
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D016227:Benzoquinones / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003114:Colony-Forming Units Assay; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D010696:Phloroglucinol / Q000031:analogs & derivatives* / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism*; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; C455139:myrtucommulone A; D010696:Phloroglucinol; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; C003466:thymoquinone
keywords: Bladder cancer; Epithelial–mesenchymal transition; Myrtucommulone-A; Rapamycin; T24; Thymoquinone; mTOR