Separase Inhibitor Sepin-1 Inhibits Foxm1 Expression and Breast Cancer Cell Growth.

Sepin-1, a potent non-competitive inhibitor of separase, inhibits cancer cell growth, but the mechanisms of Sepin-1-mediated growth inhibition are not fully understood. Here we report that Sepin-1 hinders growth of breast cancer cells, cell migration, and wound healing. Inhibition of cell growth induced by Sepin-1 in vitro doesn't appear to be through apoptosis but rather due to growth inhibition. Following Sepin-1 treatment caspases 3 and 7 are not activated and Poly (ADP-ribose) polymerase (Parp) is not cleaved. The expression of Forkhead box protein M1 (FoxM1), a transcription factor, and its target genes in the cell cycle, including Plk1, Cdk1, Aurora A, and Lamin B1, are reduced in a Sepin-1-dependent manner. Expressions of Raf kinase family members A-Raf, B-Raf, and C-Raf also are inhibited following treatment with Sepin-1. Raf is an intermediator in the Raf-Mek-Erk signaling pathway that phosphorylates FoxM1. Activated FoxM1 can promote its own transcription via a positive feedback loop. Sepin-1-induced downregulation of Raf and FoxM1 may inhibit expression of cell cycle-driving genes, resulting in inhibition of cell growth.