Ziyuglycoside II suppressed the progression of osteosarcoma by coordinating estrogen-related receptor gamma and p53 signaling pathway

Background Ziyuglycoside II (ZYG II), a triterpenoid saponin extracted from S. officinalis, has recently been found to exhibit antitumor activity. Estrogen-related receptor Gamma (ESRRG) is a set of transcription factors, which contributes significantly to the progression of an array of human malignancies. However, there is limited research on the potential of ZYG II and ESRRG in treating osteosarcoma (OS). Purpose The objective of this study is to evaluate the antitumor effect of ZYG II on osteosarcoma and to further clarify its molecular mechanism. Methods CCK-8 and EdU assay were utilized to probe the cellular vitality of cancer cells. ESRRG shRNA was employed to construct stable ESRRG-reducing OS cell lines. Flow cytometry was employed to detect the pattern of cell cycle and cell apoptosis of OS cells. In vivo, orthotopic xenograft model of osteosarcoma was used. ZYG II was given at low, medium and high doses for 28 days. H&E staining was employed to delineate the pathologic transformations of ZYG II in OS tissues. Immunohistochemistry (IHC) was utilized to examine the expression of ESRRG protein in tumor tissues. The binding of ZYG II to ESRRG protein was analyzed by molecular docking simulation. The Western blotting was utilized to analyze protein expression levels. Results Administration of ZYG II resulted in a decrease of viability of OS cells, and a reduced of tumor volumes. In addition, cell cycles were arrested at the G0/G1 phase, while the proportions of apoptotic cells increased. Furthermore, expression of p53, ESRRG, p21, Bax, Cleaved Caspase-9 and Cleaved Caspase-3 proteins were increased and expression of CDK4, Cyclin D1 and Bcl-2 proteins were reduced. Multiple ZYG II and ESRRG docking patterns were simulated by molecular docking. By comparing the pharmacodynamic response of ZYG II to OS cell lines with reduced ESRRG and normal expression, it was demonstrated that ZYG II inhibits the progression of osteosarcoma, leads to cell cycle arrest and promotes cell apoptosis through coordinating of p53 and ESRRG. Conclusion ZYG II inhibits the progression of osteosarcoma, leads to cell cycle arrest and promotes cell apoptosis through synergistic regulation of p53 and ESRRG.