Pristimerin induces Noxa-dependent apoptosis by activating the FoxO3a pathway in esophageal squamous cell carcinoma

Background: Pristimerin, which is one of the compounds present in Celastraceae and Hippocrateaceae, has antitumor effects. However, its mechanism in esophageal squamous cell carcinoma (ESCC) is still unclear. Purpose: To explore the efficacy and mechanism of pristimerin on ESCC in vitro and in vivo. Study Methods: We detected the inhibitory effect of pristimerin on cell growth by trypan blue exclusion and colony formation assays. Cell apoptosis was assessed by flow cytometry. Gene and protein expression were determined by qRT‒PCR, western blotting and immunohistochemistry. Significantly differentially expressed genes were identified via RNA-seq. Cell transfection and RNA interference assays were used to examine the role of key proteins in the effect of pristimerin. Xenograft models were established to assess the anti-tumor efficiency of pristimerin in vivo. Results: The results indicated that pristimerin inhibited cell growth and induced apoptosis in ESCC cells. Noxa upregulation was essential for pristimerin-induced apoptosis. Pristimerin activated the FoxO3a signaling pathway and triggered the recruitment of FoxO3a to the Noxa promoter, thus leading to the transcription of Noxa. Moreover, blockage of FoxO3a reversed pristimerin-induced Noxa upregulation and cell apoptosis. Pristimerin treatment suppressed xenograft tumors in nude mice, whereas these effects were nearly abolished in Noxa-KO tumors. Moreover, the in vitro and in vivo chemosensitization effects of pristimerin were mediated by Noxa. Conclusion: Our findings demonstrated that pristimerin exerted an antitumor effect on ESCC by inducing AKT/FoxO3a-mediated Noxa upregulation. Thus, pristimerin may be a potent anticancer agent for ESCC treatment.