title: Novel anti-cancer agent myrtucommulone-A and thymoquinone abrogate epithelial-mesenchymal transition in cancer cells mainly through the inhibition of PI3K/AKT signalling axis.
abstract: Epithelial-mesenchymal transition (EMT) plays a prominent role in cancer progression and metastasis. Inhibition of EMT-associated regulators may hold a huge promise for cancer therapy. Although TGF-β signalling has a pivotal role in the induction of EMT, alterations during the EMT process are usually initiated and controlled by the cross-talk of multiple signalling pathways, and in most cases this is context-dependent. In the present study, we aimed at identifying the molecular mechanisms during the inhibition of EMT by novel anti-cancer agent myrtucommulone-A (MC-A) and thymoquinone (TQ). We used epithelial cancer cells to study the effects of MC-A and TQ on EMT. We first showed the functional inhibition of EMT by MC-A or TQ using migration assays and confirmed the EMT inhibition by analysing the expression of EMT markers with RT-PCR, immunocytochemistry and Western blotting. We evaluated the changes in intracellular dynamics by Western blotting and compared the effects of MC-A and TQ with the effects of selective inhibitors of PI3K (LY294002), ERK 1/2 (U0126) and TGF-βR (SB431542). We demonstrate that both MC-A and TQ treatment negatively regulate the EMT process through modulation of signalling pathways in cancer cells. MC-A and TQ treatment inhibited phosphorylation of multiple proteins in a context-dependent manner. Novel anti-cancer agent MC-A and TQ regulate distinct signalling pathways for the repression of EMT which emphasises the significance of combinational therapies in cancer treatment. MC-A and TQ could be considered as candidate molecules for combinational therapies with their ability to interfere signalling pathways regulating cancer cell behaviour.
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: Halit
authors.initials: H
authors.lastname: Canatan
mesh_terms: D016227:Benzoquinones / Q000494:pharmacology*; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005260:Female; D006801:Humans; D008297:Male; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D010696:Phloroglucinol / Q000031:analogs & derivatives* / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D016227:Benzoquinones; D010696:Phloroglucinol; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; C455139:myrtucommulone A; C003466:thymoquinone
keywords: Epithelial cancer cells; Epithelial–mesenchymal transition; HTB-9; MDA-MB-231; Myrtucommulone-A; PI3K/AKT pathway; Thymoquinone