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Pancreatic cancer is characterized by aggressive and highly metastatic phenotypes. This disease exhibits a poor patient prognosis and is considered a challenge due to the limited treatment options encountered in clinical practice. Previous studies have shown that ruscogenin, a saponin found in the root of Ophiopogon japonicus, exerts a wide range of biological functions including anticancer activity. In the present study, the effects of ruscogenin were investigated on pancreatic cancer cells and the potential molecular mechanism of this compound was explored. Cell viability was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cell death was measured by trypan blue staining and by flow cytometry. The number of iron oxide nanoparticles was measured using Prussian blue staining. Reactive oxygen species (ROS) production was assessed using flow cytometry with dihydroethidium staining. Protein expression of the associated genes was assayed by western blotting. Furthermore, in vivo experiments were conducted to confirm the antitumor effects and assay the potential toxicity of ruscogenin in a nude mouse xenograft model. The results indicated that ruscogenin significantly repressed cell viability and induced cell death of pancreatic cancer cells in vitro in a dose-and time-dependent manner. Furthermore, ruscogenin increased the concentration of intracellular ferrous irons and the production of ROS. This effect was inhibited by deferoxamine (DFO). Ruscogenin induced ferroptosis by regulating the levels of transferrin and ferroportin. These two proteins were involved in ruscogenin-induced pancreatic cancer cell death. Finally, in vivo experiments demonstrated the antitumor effect of ruscogenin on pancreatic cancer xenografts in the absence of apparent toxicity. Taken collectively, the data demonstrated that ruscogenin exhibited anticancer effects in pancreatic cancer cells by inducing ferroptosis. The findings suggested that this compound may be further developed as a promising anticancer candidate for the treatment of pancreatic cancer.

Background: Pancreatic cancer (PC) is one of the most aggressive cancers and has an extremely poor prognosis worldwide. Long noncoding RNA (lncRNA) has been reported to be a potential prognostic biomarker in the initiation and prognosis of PC. Nevertheless, the biological functions and the detailed molecular mechanism of LINC00514 in PC remain unclear. Methods: We measured the expression level of LINC00514 in PC tissues and cell lines by quantitative real-time PCR. Gain-and loss-of-function experiments were performed to explore the bioeffects of LINC00514 on PC development both in vitro and in vivo. Subcellular fractionation, luciferase reporter assay, RNA immunoprecipitation assay, pulldown assay and western blotting were performed to investigate the oncogenic molecular mechanisms of LINC00514. Results: In this study, LINC00514 was shown to be upregulated in PC tissues and cell lines. Increased LINC00514 expression was significantly associated with the clinical progression and prognosis of PC patients. In addition, silencing LINC00514 inhibited PC cell proliferation, migration and invasion, while LINC00514 overexpression promoted these processes. Moreover, LINC00514 knockdown remarkably inhibited PC development and metastasis in vivo. Deeper investigations indicated that LINC00514 acted as a sponge for microRNA-28-5p (miR-28-5p) in PC and that Rap1b was a downstream target of miR-28-5p. Furthermore, the positive correlation of LINC00514 and Rap1b and the negative correlation between miR-28-5p and LINC00514 (or Rap1b) were revealed. Based on the rescue assays, Rap1b inhibition partially suppressed the oncogenic effect of LINC00514 overexpression on PC cell proliferation, migration and invasion. Conclusions: This study is the first to characterize the oncogenic function of the long noncoding RNA LINC00514 in pancreatic cancer progression by acting as a competing endogenous RNA (ceRNA) of miR-28-5p to upregulate Rap1b expression. Understanding this molecular mechanism might contribute to further discoveries of better diagnostic and therapeutic options for pancreatic cancer.

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