Agrimonolide induces endoplasmic reticulum stress-driven immunogenic cell death in ovarian cancer by reducing PFKFB3 expression

Background Endoplasmic reticulum stress (ERS)-driven immunogenic cell death (ICD) has been proven to be a highly promising approach for cancer treatment. Agrimonolide (Agr) has been confirmed to play an anti-tumor role in ovarian cancer (OC). However, whether Agr inhibits OC progression by regulating ERS-driven ICD remains unknown. Methods OC cells were treated with different concentrations of Agr and co-cultured with dendritic cells (DC). Cell proliferation was measured with CCK8 and colony formation assay. Flow cytometry was used to test cell apoptosis, calreticulin level, and DC maturation. The levels of ERS-related markers, DC activation markers and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) were examined using western blot or qRT-PCR. A mouse tumor model was constructed to evaluate the effect of Agr on OC tumor growth. Results Agr repressed OC cell proliferation, enhanced apoptosis, induced ERS-driven ICD and DC activation. Furthermore, Agr inhibited OC tumor growth, induced ERS-driven ICD, and activated the anti-tumor immune response. In terms of mechanism, Agr targeted PFKFB3 to reduce its mRNA stability and protein expression. In addition, Agr suppressed OC cell growth by inducing ERS-driven ICD via downregulating PFKFB3. Conclusion Agr induced ERS-driven ICD to inhibit OC cell growth and tumorigenesis by repressing PFKFB3 expression, providing a potential molecular mechanism for understanding the anti-tumor effects of Agr in OC.