MyD88 Inhibitor ST2825 Induces G2/M Cell Cycle Arrest And Apoptosis Via Suppressing NF-?B And ERK Pathways In Pancreatic Cancer

Backgrounds:Pancreatic cancer,as a dangerous malignant tumor,although its incidence worldwide is lower than liver cancer,but has a low mortality rate due to its low chance of surgery and limited effects of conventional chemotherapy.Therefore,in recent decades,researchers have been working hard to find effective targeted therapy sites,of which NF-?B is an important target.NF-?B activation occurs in most(67�70%)patients of pancreatic ductal adenocarcinoma(PDAC),however directly targeting NF-?B proteins by small-molecule inhibitors has proven unsuccessful,but recent studies shows a certain effect on the indirect inhibition of NF-?B such as IL-1alpha R and IKK.MyD88 is a common intermediate messenger for NF-?B activation by inducers like TNF-alpha,IL-1alpha,and TLR family members.This article aims to explore the expression level of MyD88 in PDAC tissues and its relationship with clinical manifestations,the effect of MyD88-specific inhibitor ST2825 on PDAC and its mechanism of action.Methods:The level of MyD88 in PDAC was detected by database and a tissue chip.We applied a specific inhibitor(ST2825)of MyD88,to explore its effects on MyD88-overexpressing PDAC cell lines.Colony-formation assay and Flow cytometry were used for examining cell proliferation,apoptosis,and cell cycle progression.Transcriptome sequencing were used for ST2825-treated Bx PC-3 cells compared with normal Bx PC-3 cells.The m RNA and protein levels of the related genes affected by ST2825 were measured by q PCR and Western Blot analysis.Chromatin Immunoprecipitation,NF-?B p65 Transcription Factor Assay and an NF-?B Phospho-Antibody Array were performed to figure out the change of NF-?B pathway as a classic transcription factor family.An subcutaneous tumor model in nude mice was used verified the effect of ST2825 on pancreatic cancer in vivo.Results:We confirmed MyD88 is overexpressed in PDAC.ST2825 could suppress cell proliferation,induce G2/M phase cell cycle arrest and apoptosis in Bx PC-3 and PANC-1cells.ST2825 inhibitsed MyD88 dimerization to inactivate NF-?B and ERK pathways,respectively.ST2825 could inhibit AKT expression and induce p21 overexpression to induce G2/M phase cell cycle arrest and apoptosis by inhibiting NF-?B transcriptional activity.ST2825 inhibited pancreatic cancer growth in nude mice,and inhibited p65 and ERK1/2 phosphorylation levels?Conclusions:Our results demonstrates that ST2825 can induce G2/M cell cycle arrest and apoptosis via NF-?B/AKT/p21 and ERK pathways in PDAC.Targeting MyD88 represents a potential therapeutic strategy for the treatment of PDAC.