ginsenoside-rh4 and Esophageal-Neoplasms

The metastasis of esophageal squamous cell carcinoma (ESCC) is a leading cause of death worldwide, however, it has a poor prognosis. Ginsenoside Rh4 is a rare saponin that has been shown to have potential antitumor effectiveness in ESCC. However, the utility of Rh4 in ESCC metastasis and its undiscovered mode of action has not yet been explored. In this study, we found that Rh4 could inhibit ESCC metastasis by regulating the Wnt/β-catenin signaling pathway and the level of c-Myc, which is an important transcription factor in cancer. In in vitro experiments, Rh4 could inhibit the migration and invasion of ESCC cells without affecting cell viability. In in vivo experiments, Rh4 restrained ESCC metastasis to the lymph nodes and lungs via the suppression of epithelial-mesenchymal transition (EMT). The Wnt agonist HLY78 promoted EMT and migration of ESCC cells, whereas treatment of Rh4 can attenuate the promotion effect of HLY78. The siRNA knocking out c-Myc can also significantly reduce the expression of EMT-related marker proteins. This study illustrates a new concept for further research on the mechanism of Rh4 in ESCC.

Topics: Cell Line, Tumor; Cell Movement; Cell Proliferation; Epithelial-Mesenchymal Transition; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Gene Expression Regulation, Neoplastic; Ginsenosides; Humans; Wnt Signaling Pathway

Ginsenoside Rh4, as a bioactive component obtained from Panax notoginseng, has excellent pharmacological efficacy especially antitumor effects. However, its anticancer effects and target mechanisms in regulating human esophageal cancer are still poorly understood. Here, the results suggested that Rh4 exhibited potent anti-esophageal cancer effects in vivo and in vitro. Flow cytometric analysis and Western Blot showed that Rh4 significantly inhibited the growth by inducing G1 phase arrest. In parallel, Rh4 inhibited aerobic glycolysis in esophageal cancer cells by hindering lactate production, glucose uptake and ATP production; reducing the extracellular acidification rate (ECAR) and oxygen consumption rate (OCR); suppressing aerobic glycolysis-related protein expression. Mechanistic studies demonstrated that AKT is a possible target of Rh4, which suppresses aerobic glycolysis. Rh4 administration resulted in AKT deregulation, whereas treatment with insulin abolished the inhibitory effect of Rh4 on aerobic glycolysis. In contrast, treatment with AKT inhibitors or siRNA that silenced AKT enhanced the inhibitory effect of Rh4 on aerobic glycolysis. Moreover, molecular docking results indicated that Rh4 was able to bind to the interdomain region of AKT. Interestingly, the results revealed that Rh4 also inhibited the expression of PD-L1 via the AKT/mTOR pathway. Taken together, our findings provide important insights into the anti-esophageal cancer effects of Rh4 via suppressing aerobic glycolysis and PD-L1 expression, which indicated Rh4 could be as promising drug for clinical treatment.

Topics: Animals; B7-H1 Antigen; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Delivery Systems; Esophageal Neoplasms; Female; Gene Expression Regulation, Neoplastic; Ginsenosides; Glycolysis; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Proto-Oncogene Proteins c-akt; Random Allocation; Xenograft Model Antitumor Assays