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

Journal of Cancer Science & Therapy
Nenggang Zhang, Debananda Pati

Abstract

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.

Citations

Jan 14, 2020·Biochemical Pharmacology·Nenggang ZhangDebananda Pati
Dec 1, 2019·Pathology, Research and Practice·Nenggang ZhangDebananda Pati
Jul 3, 2021·International Journal of Molecular Sciences·Jisha AntonyJulia A Horsfield

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Methods Mentioned

BETA
protein array
nuclear translocation
GTPases

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