Novel anti-cancer agent myrtucommulone-A and thymoquinone abrogate epithelial-mesenchymal transition in cancer cells mainly through the inhibition of PI3K/AKT signalling axis


Iskender B. , Izgi K., CANATAN H.

MOLECULAR AND CELLULAR BIOCHEMISTRY, vol.416, no.1-2, pp.71-84, 2016 (Journal Indexed in SCI) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 416 Issue: 1-2
  • Publication Date: 2016
  • Doi Number: 10.1007/s11010-016-2697-y
  • Title of Journal : MOLECULAR AND CELLULAR BIOCHEMISTRY
  • Page Numbers: pp.71-84
  • Keywords: Epithelial cancer cells, HTB-9, MDA-MB-231, Epithelial-mesenchymal transition, PI3K/AKT pathway, Myrtucommulone-A, Thymoquinone, BETA-CATENIN, TGF-BETA, PATHWAYS, METASTASIS, ACTIVATION, INVASION, GROWTH, AKT, MIGRATION, 3-KINASE

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-beta 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 anticancer 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-beta R (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.