I157172, a novel inhibitor of cystathionine γ-lyase, inhibits growth and migration of breast cancer cells via SIRT1-mediated deacetylation of STAT3.

Abstract

Cystathionine γ-lyase (CSE) is highly expressed in breast cancer, and can promote breast cancer development and progression; therefore, inhibitors of CSE may be of great significance for the treatment of breast cancer. The present study identified the CSE inhibitor I157172 through virtual screening and confirmed its activity. Subsequently, the effects and mechanism of I157172 on breast cancer cells were investigated. MTS and 5-ethynyl-2 -deoxyuridine (EdU) assays were used to assess cell viability and proliferation. Scratch wound and Transwell assays were conducted to determine cell migration and invasion. In addition, H2S determination was performed using the methylene blue method, and western blotting was performed to detect protein expression. The results revealed that I157172 significantly inhibited the growth, proliferation and migration of MCF7 breast cancer cells in a dose-dependent manner. The results of further mechanistic studies demonstrated that CSE expression was negatively associated with sirtuin 1 (SIRT1) in human breast cancer tissues and cells, and CSE knockdown resulted in an increase in SIRT1 expression, and a decrease in acetylated (acetyl)-signal transducer and activator of transcription 3 (STAT3) and phosphorylated (p)-STAT3 levels in MCF7 cells. Furthermore, STAT3 downstream proteins B-cell lymphoma 2, p-protein kinase\xa0B, matrix metalloproteinase (MMP)-2 and MMP-9 were inhibited in CSE knockdown MCF7 cells. In addition, I157172 induced upregulation of SIRT1, and downregulation of acetyl-STAT3 and p-STAT3 (Tyr705), as well as inhibition of STAT3 downstream proteins. Taken together, I157172 inhibited the growth, proliferation and migration of breast cancer cells via upregulating SIRT1, which consequently mediated deacetylation of STAT3 and inactivation of the STAT3 pathway.