Targeting ER Stress with Saikosaponin A to Overcome Resistance under Radiation in Gastric Cancer Cells

Saikosaponin A is a triterpene saponin and a potentially bioactive compound derived from Bupleurum falcatum L. However, the molecular mechanisms and effects of saikosaponin A in gastric cancer remain unknown. In the present study, I evaluated the effects of saikosaponin A on cell death and endoplasmic reticulum stress via calcium and reactive oxygen species release. Targeting reactive oxygen species with diphenyleneiodonium and N-acetylcysteine inhibited cell death and protein kinase RNA-like ER kinase signaling pathway by down-regulating Nox4 and inducing glucose-regulated protein 78 exosomes. Furthermore, saikosaponin A caused a synergistic inhibitory effect of the epithelial mesenchymal transition phenomenon, indicating the reversible phenotype modulation by epithelial cells under radiation exposure in radiation-resistant gastric cancer cells. These results suggest that saikosaponin A-mediated calcium and reactive oxygen species-induced endoplasmic reticulum stress overcome radio-resistance and induce cell death under radiation in gastric cancer cells. Therefore, saikosaponin A in combination with radiation may be a potential strategy for gastric cancer therapy.