Terrein inhibits migration of human breast cancer cells via inhibition of the Rho and Rac signaling pathways

Abstract

Breast cancer is the most common cancer in women worldwide. Progression and aggressiveness of breast cancer is usually associated with its migration and invasion abilities. Recently, natural products with potential anticancer activity have become attractive candidates for alternative treatment of cancer. A fungal metabolite, terrein, isolated from the Aspergillus terreus has been revealed to exhibit selective anticancer activity; although this molecule has a variety of biological activities. The inhibitory effect on cell proliferation in hepatoma, keratinocytes, and lung cancer cells was due to cell cycle arrest without induction of apoptosis. In contrast, its effects on cervical and breast cancer cells were mediated through activation of the apoptotic process. However, the effect of terrein on cell migration and invasion has not been explored. In the present study we analyzed the molecular effects of terrein on cell adhesion, cell migration, and cell invasion using two breast cancer cell lines, MCF-7 and MDA-MB-231, which exhibit different levels of invasiveness. Terrein induced apoptosis in both breast cancer cell lines in a dose-dependent manner. In addition, at a non-toxic concentration terrein exhibited a weak inhibition of cell adhesion, using either fibronectin or type IV collagen as substrates. Notably, terrein significantly inhibited both the migration and invasion abilities of MDA-MB-231 cells at the same non-toxic concentration. A marked decrease in MMP-2 and MMP-9 transcripts, as evaluated by real-time PCR, confirmed the anti-invasion effect of terrein at the transcriptional level. Western blot analyses revealed that terrein treatment suppressed RhoB expression and reduced Rac1 phosphorylation, leading to Rho GTPase inhibition. In addition, terrein-treated MCF-7 and MDA-MB-231 cells both displayed a scattered pattern of migration, suggesting that the suppression of RhoB and Racl disturbed the collective migration processes of breast cancer cells.