Invasion and migration of MDA‐MB‐231 cells are inhibited by block of AhR and NFAT: role of AhR/NFAT1/β4 integrin signaling.

Shadboorestan, Amir; Tarfiei, Ghorban Ali; Montazeri, Hamed; Sepand, Mohammad Reza; Zangooei, Mohammad; Khedri, Azam; Ostad, Seyed Nasser; Ghahremani, Mohammad Hossein

Benzo[α]pyrene (BaP) can have significant role in the development of breast cancer via aryl hydrocarbon receptor (AhR) activation. AhR activation has been studied in several functions such as survival, migration and invasion of cancer cells. In cancer, integrins contribute to the migration/invasion process and are regulated by nuclear factor of activated T cells (NFAT) and transforming growth factor (TGF) beta pathways. The aim of the present study was to examine the effect of BaP, an activator of AhR and cyclosporine A (CsA), as inhibitor of NFAT on migration and invasion of MDA‐MB‐231 cells. Furthermore, the effects of BaP and CsA were evaluated regarding the crosstalk of AhR, NFAT1 and TGF‐β receptor 1 signaling. Treatment of MDA‐MB‐231 with BaP resulted in significantly more live cells in low doses; however, blocking NFAT with CsA decreased the viability of the cells. Activation of AhR by BaP induced invasion as well as migration in MDA‐MB‐231 cells, which was blocked by AhR antagonist. Unlike BaP, block of NFAT with CsA inhibited cell migration and cell invasion. In these cells, BaP significantly reduced AhR expression while this reduction was reversed by CH‐223191; however, CsA treatment lowered the AhR expression only at low dose. The level of β4 integrin was significantly reduced by CsA at 1 and 2.5 μm. Protein levels of Snail and TGF‐β receptor 1 were not significantly altered by BaP and CsA treatments. Considering these findings, the low AhR expression and high β4 integrin level following BaP and/or CsA treatments may contribute to the higher invasion/migration in MDA‐MB‐231 cells. Aryl hydrocarbon receptor (AhR) activation is involved in cancer and the NFAT and TGFβ pathways can regulate cancer cells. We found that benzo[α]pyrene increased the cell viability and block of NFAT with cyclosporine decreased it. The induced invasion/migration of MDA‐MB‐231 and reduced AhR expression by BaP was blocked by AhR antagonist. Cyclosporine inhibited migration/invasion, lowered AhR and β4 integrin expressions. Thus, low AhR expression and high β4 integrin level following BaP and/or CsA treatments may contribute to the higher invasion/migration.

CELL migration; ARYL hydrocarbon receptors; NUCLEAR factor of activated T-cells; BENZOPYRENE; INTEGRINS

Journal of Applied Toxicology, 2019, Vol 39, Issue 2, p375

0260-437X

Academic Journal

10.1002/jat.3728