Elaiophylin Targets EIF4B to Regulate the Proliferation, Invasion, and Apoptosis of Esophageal Squamous Cell Carcinoma via the PI3K/AKT Signaling Pathway

Abstract Background Esophageal cancer remains a dominating cause of cancer-associated death and has shown a sharp increase of more than 6-fold increase rates all over the world. It is divided into two main pathological types: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). Most of the patients are diagnosed at the advanced stage with distant metastasis and poor prognosis. Thus, it is urgent for us to identify new more effective drugs to improve the prognosis of patients with esophageal cancer. Elaiophylin is a novel autophagy inhibitor at the late stage, which is a C2 symmetric macrolides separated from Streptomyces Niger. It was proved to have anti-tumor ability of various of cancers, yet little is known whether it could inhibit the progression of esophageal squamous cancer. The study is aimed to explore the effect of Elaiophylin on ESCC. Methods The protein expression level was detected by western blot assay. The viability of ESCC cells was detected by CCK8 assay. The proliferation rate was measured by ki67 and BrdU immunofluorescent staining. The migratory ability of ESCC cells was identified by transwell assay. The apoptosis rate of ESCC cells was explored by Annexin V/PI analysis. And the genes might be regulated by Elaiophylin was analyzed by RNA-seq assay and human cancer pathway phosphorylation antibody array then verified by RT-qPCR and western blot assay. The experiments in vivo were conducted by subcutaneous into tumor in BALB/C-Nu mice. Results In the study, we firstly found that the Elaiophylin was an autophagy inhibitor at the late stage in ESCC cells which is consistent with the previous studies. In addition, Elaiophylin can inhibit the proliferation and migration of ESCCs, and accelerate its apoptosis. And the activity of PI3K/AKT pathway was inhibited by Elaiophylin, the mRNA and protein expression level of EIF4B was both downregulated by Elaiophylin. In addition, When PI3K/AKT and autophagy signaling pathway was inhibited, the expression of EIF4B was subsequently abrogated. Mechanistically, silencing of EIF4B could inhibit the proliferation and migration of ESCC cells and promoted apoptosis, which could be rescued by EIF4B-OE. Moreover, EIF4B overexpression suppressed the apoptosis, while increased the proliferation and migration of ESCC cells which resulted from Elaiophylin. Also, the EIF4B overexpression reversed the autophagic inhibition caused by Elaiophylin. Finally, Elaiophylin could inhibit the proliferation of esophageal cancer in vivo compared to the control group. Conclusions Together, our results indicated that Elaiophylin is an autophagy inhibitor governing growth and migratory ability of ESCC cells through PI3K/AKT signaling pathway and inhibit the proliferation of esophageal tumor in vivo. simultaneously, and identified EIF4B as a target of Elaiophylin, which might provide a new therapeutic strategy for esophageal squamous cell carcinoma.