Inhibition of benzo( a )pyrene‐induced cell cycle progression by all‐ trans retinoic acid partly through cyclin D1/E2F‐1 pathway in human embryo lung fibroblasts

Benzo( a )pyrene [B( a )P] is a potent environmental carcinogen, which induces cell cycle changes. All‐ trans retinoic acid (ATRA) is a promising agent in prevention and treatment of human cancers. In the present study, we investigated the inhibition of B( a )P‐induced cell cycle progression by ATRA in human embryo lung fibroblast (HELF). Our results showed that after treatment with B( a )P, the expression of cyclin D1 and E2F‐1 were both increased significantly in HELF. There were almost no changes of CDK4 and E2F‐4 expression by treatment with B( a )P. As expected, pretreatment with ATRA could efficiently decrease B( a )P‐induced overexpression of cyclin D1 and E2F‐1. In a further study, we stably transfected antisense cyclin D1 and antisense CDK4 plasmid into HELF. The inhibition of cyclin D1 expression and the inhibition of CDK4 expression significantly impaired the B( a )P‐induced overexpression of E2F‐1 respectively. Pretreatment with ATRA, cells expressing antisense cyclinD1 or antisense CDK4 showed a lesser decrease of B( a )P‐induced overexpression of E2F‐1 compared with similarly treated HELF. Furthermore, flow cytometry analysis showed that B( a )P promoted cell cycle progression from G 1 phase to S phase, while pretreatment with ATRA could inhibit B( a )P‐induced cell cycle progression by an accumulation of cells in the G 1 phase. It was suggested that ATRA could block B( a )P‐induced cell cycle promotion partly through the cyclin D1/E2F‐1 pathway in HELF.