The MyD88 inhibitor, ST2825, induces cell cycle arrest and apoptosis by suppressing the activation of the NF‑κB/AKT1/p21 pathway in pancreatic cancer.

Abstract

NF‑κB activation occurs in the majority patients with pancreatic ductal adenocarcinoma (PDAC); however, directly targeting NF‑κB has proven unsuccessful, and recent studies have demonstrated a certain effect of the indirect inhibition of NF‑κB. Myeloid differentiation factor 88 (MyD88) is a common intermediate messenger for NF‑κB activation by inducers. In the present study, the level of MyD88 in PDAC was detected using a public database and a tissue chip. A specific inhibitor (ST2825) of MyD88 was used on PDAC cell lines. Flow cytometry was used to examine apoptosis and cell cycle progression. Transcriptome sequencing was used for ST2825‑treated PANC‑1 cells compared with untreated PANC‑1 cells. The levels of related factors were measured using reverse transcription‑quantitative PCR and western blot analysis. Chromatin immunoprecipitation, co‑immunoprecipitation, transcription factor assay and an NF‑κB phospho‑antibody array were performed to identify the detailed underlying mechanisms. Animal experiments were performed to verify the effects of ST2825 on PDAC, which were found in the invitro experiments. MyD88 was found to be overexpressed in PDAC. ST2825 induced the G2/M phase cell cycle arrest and apoptosis of PDAC cells. ST2825 inhibited MyD88 dimerization to inactivate the NF‑κB pathway. ST2825 inhibited AKT1 expression and induced p21 overexpression to induce G2/M phase cell cycle arrest and apoptosis by inhibiting NF‑κB transcriptional activity. NF‑κB activation, AKT1 overexpression or p21 knockdown partially reversed the effects of ST2825 in PDAC. On the whole, the findings of the present study demonstrate that ST2825 induces G2/M cell cycle arrest and apoptosis via the MyD88/NF‑κB/AKT1/p21 pathway in PDAC. MyD88 may thus serve as a potential therapeutic target in PDAC. ST2825 may serve as a novel agent for the targeted therapy of PDAC in the future.