Association of cell cycle arrest with anticancer drug-induced epithelial-mesenchymal transition in alveolar epithelial cells

摘要

Many drugs exert serious cytotoxic effects on pulmonary tissues. Although several reports have shown an association of epithelial-mesenchymal transition (EMT) with anticancer drug-induced lung injury, mechanisms of these effects are poorly understood. In the present study, we evaluated mechanisms of anticancer drug-induced EMT, with a focus on involvement of cell cycle arrest. We found that methotrexate (MTX) altered mRNA expression levels of many genes as determined by microarray analysis. Gene set enrichment analysis revealed that cell cycle arrest pathways may be associated with MTX-induced EMT. In addition, thymidine (THY) and nocodazole (NOC), which induce cell cycle arrest at S-phase and G2/M-phase, increased mRNA expression levels of alpha-smooth muscle actin (SMA), an EMT marker. Furthermore, alpha-SMA protein expression in cells arrested at S- and G2/M-phases by MTX and paclitaxel (PTX) was significantly higher than that in cells at G1. Notably, co-treatment of cells with THY or NOC and EMT-inducing anticancer drugs did not result in additional upregulation of alpha-SMA mRNA expression. These findings suggested that cell cycle arrest may be closely associated with anticancer drug-induced EMT in alveolar epithelial cells.