Mo1938 Survivin Inhibitor YM155 Inhibits Cell Miration and Invasion in Gastric and Colon Cancer Cells Through Inhibition of Metastasis-Related Genes

Abstract

Background: Aurora kinase A (AURKA) is a serine-threonine kinase that is amplified and/ or overexpressed in several cancers. STAT3 is an important transcription factor that regulates several cytokines, growth factors, and proteins that modulate various cellular events; including survival, cell cycle, invasion, and angiogenesis. Methods and Results: In this study, by using in vitro human cell models of upper gastrointestinal adenocarcinomas (UGCs), we investigated whether AURKA can regulate STAT3.WB analysis show that AURKA overexpression led to increase in p.STAT3 (Tyr705) in FLO-1 and AGS cells. On the other hand, AURKA knockdown by siRNA resulted in decrease in p.STAT3 (Tyr705) in FLO-1 and MKN45 cells. Further, STAT3 transcriptional activity was significantly (P=0.01) up regulated in response to AURKA overexpression in the three cell lines. Consistently, AURKA overexpression significantly (P=0.01) enhanced STAT3 nuclear translocation in AGS cells, whereas AURKA knockdown significantly (P=0.01) decreased the nuclear positive stating of STAT3 in FLO-1 cells. By using alisertib (0.5 μM), an investigational AURKA specific inhibitor, we demonstrate that AURKA inhibition results in decreased phosphorylation of STAT3 (Tyr705) as early as 30 min after treatment in all cell lines. Additionally, extended treatment time points of 72 h reduced the phosphorylation of STAT3 and importantly reduced the expression of its pro-survival targets BCL2 and Mcl1 in AGS and FLO-1 cells. Clonogenic survival assay data showed that single dose treatment of alisertib for 24 h (0.5 μM), led to significant decrease in colonies intensity in AGS and FLO-1 cells. To elucidate how AURKA regulates STAT3, we investigated whether JAK2 kinases expressions changed in response to AURKA